TENORETIC

INDICATIONS AND USAGE TENORETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including atenolol and chlorthalidone. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive 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 (e.g., on 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.

DOSAGE AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. (See INDICATIONS AND USAGE .) Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of atenolol is 50 mg daily. Therefore, the initial dose should be one TENORETIC 50 tablet given once a day. If an optimal response is not achieved, the dosage should be increased to one TENORETIC 100 tablet given once a day. When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure. Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m 2 (normal range is 100 mL/min/1.73m 2 to 150 mL/min/1.73m 2 ); therefore, the following maximum dosages are recommended for patients with renal impairment. Creatinine Clearance (mL/min/1.73m 2 ) Atenolol Elimination Half-Life (hrs) Maximum Dosage 15-35 16-27 50 mg daily <15 >27 50 mg every other day

WARNINGS Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. IN PATIENTS WITHOUT A HISTORY OF CARDIAC FAILURE, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, TENORETIC should be withdrawn. (See DOSAGE AND ADMINISTRATION .) Renal and Hepatic Disease and Electrolyte Disturbances Since atenolol is excreted via the kidneys, TENORETIC should be used with caution in patients with impaired renal function. In patients with renal disease, thiazides may precipitate azotemia. Since cumulative effects may develop in the presence of impaired renal function, if progressive renal impairment becomes evident, TENORETIC should be discontinued. In patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. TENORETIC 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 TENORETIC is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum. TENORETIC should be reinstated if withdrawal symptoms occur. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue TENORETIC 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, TENORETIC 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 TENORETIC 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 Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 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 clin…

CONTRAINDICATIONS TENORETIC is contraindicated in patients with: sinus bradycardia; heart block greater than first degree; cardiogenic shock; overt cardiac failure (see WARNINGS ); anuria; hypersensitivity to this product or to sulfonamide-derived drugs.

Drug Interactions TENORETIC may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with TENORETIC plus a catecholamine depletor (e.g., reserpine) should be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope or postural hypotension. Calcium channel blockers may also have an additive effect when given with TENORETIC. (See WARNINGS .) Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta-blockers. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta-blockers. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of norepinephrine. 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 TENORETIC. 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.

Pregnancy See WARNINGS - Pregnancy and Fetal Injury .

Nursing Mothers Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the concentration in plasma. Caution should be exercised when atenolol is administered to a nursing woman. Clinically significant bradycardia has been reported in breastfed infants. Premature infants, or infants with impaired renal function, may be more likely to develop adverse effects. 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 TENORETIC is administered during pregnancy or to a woman who is breastfeeding. (See WARNINGS, Pregnancy and Fetal Injury . )

ADVERSE REACTIONS TENORETIC is usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. The adverse effects observed for TENORETIC are essentially the same as those seen with the individual components. Atenolol The frequency estimates in the following table were derived from controlled studies in which adverse reactions were either volunteered by the patient (US studies) or elicited, e.g., by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects for atenolol and placebo is similar, causal relationship to atenolol is uncertain. Volunteered (US Studies) Total − Volunteered and Elicited (Foreign + US Studies) Atenolol (n = 164) % Placebo (n = 206) % Atenolol (n = 399) % Placebo (n = 407) % CARDIOVASCULAR Bradycardia 3 0 3 0 Cold Extremities 0 0.5 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. TENORETIC, 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 TENORETIC conducted in the United States (89 patients treated with TENORETIC) revealed no new or unexpected adverse effects. POTENTIAL ADVERSE EFFECTS In addition, a variety of adverse effects not observed in clinical trials with atenolol but reported with other beta-adrenergic blocking agents should be considered potential adverse effects of atenolol. Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, decreased performance on neuropsychometrics; Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS ); Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis; Hematologic: Agranulocytosis; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm and respiratory distress. Miscellaneous There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small, and, in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy. (See DOSAGE AND ADMINISTRATION .) The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with atenolol (TENO…