CORZIDE (Nadolol and Bendroflumethiazide Tablets) for oral administration combines two antihypertensive agents: CORGARD® (nadolol), a nonselective beta-adrenergic blocking agent, and NATURETIN® (bendroflumethiazide), a thiazide diuretic-antihypertensive. Formulations: 40 mg and 80 mg nadolol per tablet combined with 5 mg bendroflu-methiazide. Inactive ingredients: cellulose, colorant (FD&C Blue No. 2), lactose, magnesium stearate, povidone, sodium starch glycolate, and starch.

Nadolol

Nadolol is a white crystalline powder. It is freely soluble in ethanol, soluble in hydrochloric acid, slightly soluble in water and in chloroform, and very slightly soluble in sodium hydroxide. Nadolol is designated chemically as 1-(tert-butylamino)-3-{(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)oxy}-2-propanol. Structural formula:

Bendroflumethiazide

Bendroflumethiazide is a white crystalline powder. It is soluble in alcohol and in sodium hydroxide, and insoluble in hydrochloric acid, water, and chloroform. Bendroflumethiazide is designated chemically as 3-benzyl-3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Structural formula:

CORZIDE (Nadolol and Bendroflumethiazide Tablets) is indicated in the management of hypertension.

This fixed combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient's needs, it may be more convenient than the separate components.

DOSAGE MUST BE INDIVIDUALIZED (SEE INDICATIONS). CORZIDE MAY BE ADMINISTERED WITHOUT REGARD TO MEALS.

Bendroflumethiazide is usually given at a dose of 5 mg daily. The usual initial dose of nadolol is 40 mg once daily whether used alone or in combination with a diuretic. Bendroflumethiazide in CORZIDE is 30 percent more bioavail-able than that of 5 mg Naturetin tablets. Conversion from 5 mg NATURETIN to CORZIDE represents a 30 percent increase in dose of bendroflumethiazide.

The initial dose of CORZIDE (Nadolol and Bendroflumethiazide Tablets) may therefore be the 40 mg/5 mg tablet once daily. When the antihypertensive response is not satisfactory, the dose may be increased by administering the 80 mg/5 mg tablet once daily.

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.

Dosage Adjustment in Renal Failure-Absorbed nadolol is excreted principally by the kidneys and, although non-renal elimination does occur, dosage adjustments are necessary in patients with renal impairment. The following dose intervals are recommended:

CORZIDE (Nadolol and Bendroflumethiazide Tablets)

• 40 mg nadolol combined with 5 mg bendroflumethiazide in bottles of 100 tablets (NDC 60793-283-01).
• 80 mg nadolol combined with 5 mg bendroflumethiazide in bottles of 100 tablets (NDC 60793-284-01).

Round, biconvex tablets are white to bluish white with dark blue specks. Each tablet has a full bisect bar. Tablet identification numbers: 40 mg/5 mg combination embossed with KPI/283 on the scored side and Corzide 40/5 on the other; 80 mg/5 mg combination embossed with KPI/284 on the scored side and Corzide 80/5 on the other.

Storage

Keep bottle tightly closed. Store at room temperature; avoid excessive heat.

Prescribing Information as of July 2007. Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620. FDA revision date: 8/6/2008

Nadolol

Most adverse effects have been mild and transient and have rarely required withdrawal of therapy.

Cardiovascular-Bradycardia with heart rates of less than 60 beats per minute occurs commonly, and heart rates below 40 beats per minute and/or symptomatic bradycardia were seen in about 2 of 100 patients. Symptoms of peripheral vascular insufficiency, usually of the Raynaud type, have occurred in approximately 2 of 100 patients. Cardiac failure, hypotension, and rhythm/conduction disturbances have each occurred in about 1 of 100 patients. Single instances of first degree and third degree heart block have been reported; intensification of AV block is a known effect of beta-blockers (see also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Central Nervous System-Dizziness or fatigue has been reported in approximately 2 of 100 patients; paresthesias, sedation, and change in behavior have each been reported in approximately 6 of 1000 patients.

Respiratory-Bronchospasm has been reported in approximately 1 of 1000 patients (see CONTRAINDICATIONS and WARNINGS).

Gastrointestinal-Nausea, diarrhea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating, and flatulence have been reported in 1 to 5 of 1000 patients.

Miscellaneous-Each of the following has been reported in 1 to 5 of 1000 patients: rash; pruritus; headache; dry mouth, eyes, or skin; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision. Reversible alopecia has been reported infrequently. The following adverse reactions have been reported in patients taking nadolol and/or other beta-adrenergic blocking agents, but no causal relationship to nadolol has been established.

Central Nervous System-Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometrics.

Gastrointestinal-Mesenteric arterial thrombosis; ischemic colitis; elevated liver enzymes.

Hematologic-Agranulocytosis; thrombocytopenic or nonthrombocytopenic purpura.

Allergic-Fever combined with aching and sore throat; laryngospasm; respiratory distress.

Miscellaneous-Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep disturbances; Peyronie's disease. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with nadolol.

Bendroflumethiazide

Gastrointestinal-Nausea, vomiting, cramping and anorexia are not uncommon; diarrhea, constipation, gastric irritation, abdominal bloating, jaundice (intrahepatic cholestatic jaundice), hepatitis, and sialadenitis occasionally occur; and pancreatitis has been reported.

Central Nervous System-Dizziness, vertigo, paresthesia, headache, and xanthopsia occasionally occur.

Hematologic-Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, and aplastic anemia have been reported.

Dermatologic-Hypersensitivity-Purpura, exfoliative dermatitis, pruritus, ecchymosis, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis, fever, and anaphylactic reactions occasionally occur; photosensitivity and rash have been reported.

Cardiovascular-Orthostatic hypotension may occur and may be potentiated by coadministration with certain other drugs (e.g., alcohol, barbiturates, narcotics, other antihypertensive medications, etc.; see PRECAUTIONS: DRUG INTERACTIONS).

Other-Muscle spasm, weakness, or restlessness is not uncommon; hyperglycemia, glycosuria, metabolic acidosis in diabetic patients, hyperuricemia, allergic glomerulonephritis, and transient blurred vision occasionally occur. Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

Nadolol

When administered concurrently the following drugs may interact with betaadrenergic receptor blocking agents:

Anesthetics, general-exaggeration of the hypotension induced by general anesthetics (see WARNINGS, Nadolol, Major Surgery).

Antidiabetic drugs (oral agents and insulin)-hypoglycemia or hyperglycemia; adjust dosage of antidiabetic drug accordingly (see WARNINGS, Nadolol, Diabetes and Hypoglycemia).

Catecholamine-depleting drugs (e.g., reserpine)-additive effect; monitor closely for evidence of hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural hypotension).

Digitalis glycosides-Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Response to Treatment for Anaphylactic Reaction-While taking beta-blockers, patients with a history of severe anaphy-lactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Bendroflumethiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, or narcotics-potentiation of orthostatic hypotension may occur.

Amphotericin B, corticosteroids, or corticotropin (ACTH)-may intensify electrolyte imbalance, particularly hypo-kalemia. Monitor potassium levels; use potassium replacements if necessary.

Anticoagulants (oral)-dosage adjustments of anticoagulant medication may be necessary since bendroflumethi-azide may decrease their effects.

Antigout medications-dosage adjustments of antigout medication may be necessary since bendroflumethiazide may raise the level of blood uric acid.

Other antihypertensive medications (e.g., ganglionic or peripheral adrenergic blocking agents)-dosage adjustments may be necessary since bendroflumethiazide may potentiate their effects.

Antidiabetic drugs (oral agents and insulin)-since thiazides may elevate blood glucose levels, dosage adjustments of antidiabetic agents may be necessary.

Calcium salts-increased serum calcium levels due to decreased excretion may occur. If calcium must be prescribed monitor serum calcium levels and adjust calcium dosage accordingly.

Cardiac glycosides-enhanced possibility of digitalis toxicity associated with hypokalemia. Monitor potassium levels; use potassium replacement if necessary.

Cholestyramine resin and colestipol HCl-may delay or decrease absorption of bendroflumethiazide. Sulfonamide diuretics should be taken at least one hour before or four to six hours after these medications.

Diazoxide-enhanced hyperglycemic, hyperuricemic, and antihypertensive effects. Be cognizant of possible interaction; monitor blood glucose and serum uric acid levels.

Lithium salts-may enhance lithium toxicity due to reduced renal clearance. Avoid concurrent use; if lithium must be prescribed monitor serum lithium levels and adjust lithium dosage accordingly. (See WARNINGS.)

MAO inhibitors-dosage adjustments of one or both agents may be necessary since hypotensive effects are enhanced.

Nondepolarizing muscle relaxants, preanesthetics and anesthetics used in surgery (e.g., tubocurarine chloride and gallamine triethiodide)-effects of these agents may be potentiated; dosage adjustments may be required. Monitor and correct any fluid and electrolyte imbalances prior to surgery if feasible.

Nonsteroidal anti-inflammatory agents-in some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing or thiazide diuretics. Therefore, when bendroflumethiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Methenamine-possible decreased effectiveness due to alkalinization of the urine.

Pressor amines (e.g., norepinephrine)-decreased arterial responsiveness, but not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both medications who undergo surgery. Administer preanesthetic and anesthetic agents in reduced dosage, and if possible, discontinue bendroflumethiazide one week prior to surgery.

Probenecid or sulfinpyrazone-increased dosage of these agents may be necessary since bendroflumethiazide may have hyperuricemic effects.

Drug/Laboratory Test Interactions

Bendroflumethiazide may produce false-negative results with the phentolamine and tyramine tests; may interfere with the phenolsulfonphthalein test due to decreased excretion; and it may cause diagnostic interference of serum electrolyte levels, blood and urine glucose levels, and a decrease in serum PBI levels without signs of thyroid disturbance.

Nadolol

Cardiac Failure-Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, they can be used with caution in patients with a history of failure who are well compensated, usually with digitalis and diuretics. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE, continued use of beta-blockers can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of heart failure, the patient should be digitalized and/or treated with diuretics, and the response observed closely, or nadolol should be discontinued (gradually, if possible).

Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)- PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. Nadolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta₂ receptors.

Major Surgery-Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, betablockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy. The effects of nadolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.

Diabetes and Hypoglycemia-Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.

Thyrotoxicosis-Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blockade which might precipitate a thyroid storm.

Bendroflumethiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lithium generally should not be given with diuretics; diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such concomitant therapy.

General

Nadolol

Nadolol should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

Bendroflumethiazide

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely: hyponatremia, hypochloremic alkalosis, and hypokalemia. 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 may include: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.

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). Concurrent administration of a potassium-sparing diuretic or potassium supplements may be indicated in these patients.

Any chloride deficit 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.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Latent diabetes mellitus may become manifest during thiazide administration.

The antihypertensive effect of thiazide diuretics may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen (BUN), a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Laboratory Tests

Serum electrolyte levels should be regularly monitored (see WARNINGS, Bendroflumethiazide, also PRECAUTIONS, General, Bendroflumethiazide).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nadolol

In chronic oral toxicologic studies (one to two years) in mice, rats, and dogs, nadolol did not produce any significant toxic effects. In two-year oral carcinogenicity studies in rats and mice, nadolol did not produce any neoplastic, pre-neoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effect.

Bendroflumethiazide

Studies have not been performed to evaluate carcinogenic potential, mutagenesis, or whether this drug adversely affects fertility in males or females.

Pregnancy-Teratogenic Effects

Nadolol

Category C. In animal reproduction studies with nadolol, evidence of embryo-and fetotoxicity was found in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species.

There are no adequate and well-controlled studies in pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.

Bendroflumethiazide

Category C. Animal reproduction studies have not been conducted with bendroflumethiazide. It is also not known whether this drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bendroflumethiazide should be given to a pregnant woman only if clearly needed.

Pregnancy-Nonteratogenic Effects

Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit 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.

Nursing Mothers

Both nadolol and bendroflumethiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of CORZIDE (Nadolol and Bendroflumethiazide Tablets) to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Corzide 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 the 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 of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reaction to this drug may be greater in patients with impaired function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

In the event of overdosage, nadolol may cause excessive bradycardia, cardiac failure, hypotension, or bronchospasm. In addition to the expected diuresis, overdosage of bendroflumethiazide may produce varying degrees of lethargy which may progress to coma with minimal depression of respiration and cardiovascular function and without significant serum electrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown. Gastrointestinal irritation may occur. Transitory increase in BUN has been reported, and serum electrolyte changes may occur, especially in patients with impaired renal function.

Treatment

Nadolol can be removed from the general circulation by hemodialysis. In determining the duration of corrective therapy, note must be taken of the long duration of the effect of nadolol. In addition to gastric lavage, the following measures should be employed, as appropriate.

Excessive Bradycardia-Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

Cardiac Failure-Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be useful in this situation.

Hypotension-Administer vasopressors, e.g., epinephrine or levarterenol. (There is evidence that epinephrine may be the drug of choice.)

Bronchospasm-Administer a beta₂-stimulating agent and/or a theophylline derivative.

Stupor or Coma-Supportive therapy as warranted.

Gastrointestinal Effects-Symptomatic treatment as needed.

BUN and/or Serum Electrolyte Abnormalities-Institute supportive measures as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.

Nadolol

Nadolol is contraindicated in bronchial asthma, sinus bradycardia and greater than first degree conduction block, cardiogenic shock, and overt cardiac failure (see WARNINGS).

Bendroflumethiazide

Bendroflumethiazide is contraindicated in anuria. It is also contraindicated in patients who have previously demonstrated hypersensitivity to bendroflumethiazide or other sulfonamide-derived drugs.

Nadolol

Nadolol is a nonselective beta-adrenergic receptor blocking agent. Clinical pharmacology studies have demonstrated beta-blocking activity by showing (1) reduction in heart rate and cardiac output at rest and on exercise, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.

Nadolol specifically competes with beta-adrenergic receptor agonists for available beta receptor sites; it inhibits both the beta₁ receptors located chiefly in cardiac muscle and the beta₂ receptors located chiefly in the bronchial and vas-cular musculature, inhibiting the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation proportionately. Nadolol has no intrinsic sympathomimetic activity and, unlike some other beta-adrenergic blocking agents, nadolol has little direct myocardial depressant activity and does not have an anesthetic-like membrane-stabilizing action. Animal and human studies show that nadolol slows the sinus rate and depresses AV conduction. In dogs, only minimal amounts of nadolol were detected in the brain relative to amounts in blood and other organs and tissues. Nadolol has low lipophilicity as determined by octanol/water partition coefficient, a characteristic of certain beta-blocking agents that has been correlated with the limited extent to which these agents cross the blood-brain barrier, their low concentration in the brain, and low incidence of CNS-related side effects.

In controlled clinical studies, nadolol at doses of 40 to 320 mg/day has been shown to decrease both standing and supine blood pressure, the effect persisting for approximately 24 hours after dosing.

The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established; however, factors that may be involved include (1) competitive antagonism of catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially cardiac) leading to decreased cardiac output, (2) a central effect leading to reduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression of renin secretion by blockade of the beta-adrenergic receptors responsible for renin release from the kidneys.

While cardiac output and arterial pressure are reduced by nadolol therapy, renal hemodynamics are stable, with preservation of renal blood flow and glomerular filtration rate.

By blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, nadolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, nadolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.

Although beta-adrenergic receptor blockade is useful in treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta₂-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bron-chospasm and may also interfere with exogenous bronchodilators in such patients.

Absorption of nadolol after oral dosing is variable, averaging about 30 percent. Peak serum concentrations of nadolol usually occur in three to four hours after oral administration and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to plasma protein.

Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys.

The half-life of therapeutic doses of nadolol is about 20 to 24 hours, permitting once-daily dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in renal failure (see PRECAUTIONS, General, and DOSAGE AND ADMINISTRATION). Steady state serum concentrations of nadolol are attained in six to nine days with once-daily dosage in persons with normal renal function. Because of variable absorption and different individual responsiveness, the proper dosage must be determined by titration.

Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.

Bendroflumethiazide

The mechanism of action of bendroflumethiazide results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency.

Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

Onset of action of thiazides occurs in two hours and the peak effect at about four hours. Duration of action persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.

Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure.

The patient should also be advised of a proper course in the event of an inadvertently missed dose.

The patient should be informed of symptoms that would suggest potential adverse effects and told to report them promptly.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NADOLOL/BENDROFLUMETHIAZIDE - ORAL

(nay-DOE-lole/ben-droe-floo-meth-EYE-a-zide)

COMMON BRAND NAME(S): Corzide

WARNING: This product contains two medications and generally, this product should not be used when treating high blood pressure (hypertension) for the first time. Each of the two different drugs in this product should first be given separately so that the best dose of each drug can be determined. This combination product should only be used if your doctor determines that the doses of each drug in this product are right for your condition. Depending on your condition, your medications may need to be adjusted by your doctor on an ongoing basis. If you have chest pain (angina) or heart disease (e.g., coronary artery disease, ischemic heart disease, high blood pressure), do not stop using this medication without first consulting your doctor. Your condition may become worse when the drug is suddenly stopped. If your doctor decides you should no longer use this drug, you must gradually decrease your dose according to your doctor's instructions.

When gradually stopping this medication, it is recommended that you temporarily limit physical activity to decrease work for the heart. Seek immediate medical attention if you develop: worsening chest pain, tightness/pressure in the chest, chest pain spreading to the jaw/neck/arm, sweating, trouble breathing, or fast/irregular heartbeat.

USES: This product is used with or without other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.

This product contains two medications. Nadolol is a beta blocker that works by blocking the effect of certain natural chemicals such as adrenaline (epinephrine) on the heart and blood vessels. This slows your heartbeat, lowers blood pressure, and reduces strain on the heart. Bendroflumethiazide is a "water pill" (diuretic) that works by increasing the amount of urine that you make. This causes your body to get rid of extra salt and water, which probably helps to relax the blood vessels so that blood can flow more easily. These two drugs are used together when one medication is not controlling your blood pressure.

HOW TO USE: See also the Warning and Drug Interactions sections.

Take this medication by mouth, usually once daily or as directed by your doctor. Take it consistently with or without food.

If you take this drug too close to bedtime, you may need to wake up to urinate. Therefore, it is best to take this medication at least 4 hours before your bedtime. Consult your doctor or pharmacist if you have questions about your dosing schedule.

The dosage is based on your age, medical condition and response to therapy. If you have severe liver or kidney problems, your dosage may need to be adjusted.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. It may take up to several weeks before the full benefit of this drug takes effect.

Do not stop taking this medication without first consulting your doctor. Some conditions may become worse when the drug is abruptly stopped. Your dose may need to be gradually decreased.

Inform your doctor if your condition worsens (e.g., your routine blood pressure readings increase).

SIDE EFFECTS: Dizziness, drowsiness, headache, temporary blurred vision, nausea, bloating, gas, constipation, diarrhea, vomiting, weight gain, or dry mouth may also occur as your body adjusts to the medication. You may also be more sensitive to sunburn (see Precautions section).

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: slow/irregular heartbeat, mental/mood changes (e.g., memory loss, depression, confusion), fainting, bluish fingers/toes/nails, decreased sexual ability, joint/muscle pain, increased urination, unusual shakiness/sweating, unusual hunger.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, black stools, persistent rectal bleeding, signs of infection (e.g., persistent sore throat, fever), yellowing of the eyes/skin, persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, slurred speech, painful erections.

This product may reduce blood flow to your hands and feet, causing them to feel cold. Smoking may worsen this effect. Dress warmly and avoid tobacco use.

Medications similar to the nadolol in this product may cause or worsen heart failure. Tell your doctor immediately if you notice any of the following unlikely but serious side effects: swelling of the ankles/feet, shortness of breath, severe tiredness, unexplained/sudden weight gain.

Nadolol can also make it easier to have symptoms of asthma (e.g., feeling of tightness in the chest, trouble breathing, wheezing, cough). Tell your doctor immediately if any of these symptoms occur.

The bendroflumethiazide in this product may cause too much body water and salts to be lost (dehydration). Tell your doctor immediately if you have any of these unlikely but serious symptoms of dehydration: very dry mouth, thirst, muscle cramps, weakness, fast heartbeat, severe dizziness, unusual decrease in the amount of urine, fainting, seizures.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: See also the Warning section.

Before taking this product, tell your doctor or pharmacist if you are allergic to nadolol or bendroflumethiazide; or to other beta blockers (e.g., atenolol, propranolol); or to other thiazides (e.g., hydrochlorothiazide); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain types of heart rhythm problems (e.g., sinus bradycardia, second- or third-degree atrioventricular block), certain serious heart conditions (cardiogenic shock, severe heart failure), severe breathing problems (asthma, chronic obstructive pulmonary disease-COPD), inability to make urine (anuria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart failure (treated, stable type), breathing problems (e.g., wheezing/cough with exercise), diabetes, overactive thyroid (e.g., hyperthyroidism), gout, blood circulation problems (e.g., Raynaud's disease, peripheral vascular disease), low blood flow to the brain (cerebral insufficiency), high levels of fats in the blood (cholesterol or triglycerides), low salts in the blood (e.g., low potassium/magnesium), loss of too much body water (dehydration), certain nerve/muscle problems (e.g., myasthenia gravis), liver problems, kidney problems, lupus, asthma, recent nerve surgery (e.g., sympathectomy).

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

To reduce dizziness and lightheadedness, get up slowly when rising from a seated or lying position. Drink plenty of fluids while taking this medication to help prevent dizziness. Too much sweating, diarrhea or vomiting may cause you to lose large amounts of water and salts, causing lightheadedness. Avoid heavy exercise. Report prolonged diarrhea or vomiting to your doctor.

This medication may reduce the potassium levels in your blood. Ask your doctor about adding potassium to your diet. A potassium supplement may be prescribed by your doctor.

If you have diabetes, this product may mask the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of a low blood sugar level, such as dizziness/sweating, are unaffected by this drug. This product may also make it harder to control your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar such as increased thirst/urination. Your anti-diabetic medication or diet may need to be adjusted.

Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially dizziness and lightheadedness.

Caution is advised when using this product in infants and children because they may be more sensitive to its side effects, especially low blood sugar.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This medication should be used only when clearly needed during pregnancy. Infants exposed to the bendroflumethiazide in this product during pregnancy may have liver or bleeding problems. Discuss the risks and benefits with your doctor.

The medications in this product pass into breast milk. The nadolol in this product may have undesirable effects on a nursing infant. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: arbutamine, cisapride, dofetilide.

If you are currently using any of these medications, tell your doctor or pharmacist before starting this product.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha blockers (e.g., prazosin), anesthesia drugs, barbiturates (e.g., phenobarbital), drugs for diabetes (e.g., glipizide, glyburide, metformin), "blood thinners" (e.g., warfarin), calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), clonidine, diazoxide, epinephrine, digoxin, fenoldopam, guanethidine, calcium supplements, lidocaine, lithium, methyldopa, MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine), narcotic pain relievers (e.g., codeine, morphine), reserpine, theophylline, tubocurarine, drugs that affect uric acid levels (e.g., probenecid, sulfinpyrazone), drugs that may cause potassium loss (e.g., amphotericin B, corticotropin, corticosteroids including prednisone), drugs whose removal from the body is affected by the level of acid in the urine (e.g., amphetamine, methenamine, quinidine).

Cholestyramine and colestipol may decrease the absorption of this medication. If you are taking either of these drugs, separate them from this medication by at least 4 hours.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, nonsteroidal anti-inflammatory drugs-NSAIDs for pain/fever reduction) because they may contain ingredients that could increase your blood pressure or cause a fast heartbeat (e.g., pseudoephedrine, phenylephrine, chlorpheniramine, diphenhydramine, clemastine, ibuprofen, naproxen). Ask your pharmacist about the safe use of those products.

This product can affect the results of certain lab tests (e.g., phentolamine test, protein-bound iodide, tyramine test, blood salt (electrolyte) levels, blood/urine glucose). Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: very slow heartbeat, severe dizziness, fainting, slow/shallow breathing, signs of low blood sugar (e.g., nervousness, shakiness, sweating, hunger).

NOTES: Do not share this medication with others.

Lifestyle changes such as stress reduction programs, exercise, and dietary changes may increase the effectiveness of this medicine. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Laboratory and/or medical tests (e.g., blood pressure, blood salt levels, liver and kidney function tests) may be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure and heart rate checked regularly while taking this medication. Learn how to monitor your own blood pressure and heart rate at home, and share the readings with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.