Nadolol / Bendroflumethiazide

Pronunciation: NAY-doe-lol/BEN-droe-FLOO-me-THYE-a-zide
Class: Antihypertensive combination

Trade Names

Corzide
- Tablets, oral nadolol 40 mg/bendroflumethiazide 5 mg
- Tablets, oral nadolol 80 mg/bendroflumethiazide 5 mg

Pharmacology

Bendroflumethiazide

Interferes with the renal tubular mechanism of electrolyte reabsorption.

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Nadolol

Blocks beta-receptors, which primarily affect the CV system (decreases heart rate, contractility, and BP) and lungs (promotes bronchospasm).

Indications and Usage

For the treatment of hypertension.

Contraindications

Anuria; bronchial asthma; cardiogenic shock; greater than first-degree conduction block; hypersensitivity to bendroflumethiazide or other sulfonamide-derived drugs; overt cardiac failure; sinus bradycardia.

Dosage and Administration

Adults

PO Nadolol 40 mg/bendroflumethiazide 5 mg once daily initially. The dosage may be increased to nadolol 80 mg/bendroflumethiazide 5 mg once daily.

Renal impairment
Adults

PO For CrCl 31 to 50 mL/min/1.73 m 2 , administer dose every 24 to 36 h. For CrCl 10 to 30 mL/min/1.73 m 2 , administer dose every 24 to 48 h. For CrCl less than 10 mL/min/1.73 m 2 , administer dose every 40 to 60 h.

General Advice

  • Administer without regard to meals
  • Nadolol/bendroflumethiazide is not indicated for initial therapy of hypertension. If the fixed combination represents the determined dosage, its use may be more convenient in patient management.
  • Another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose.
  • When discontinuing therapy, gradually reduce dosage over a period of 1 to 2 wk; do not discontinue therapy abruptly.

Storage/Stability

Store at room temperature. Avoid excessive heat.

Drug Interactions

No drug interaction studies have been conducted between nadolol/bendroflumethiazide and other drugs. The following interactions are based on drug interactions involving each component of the nadolol/bendroflumethiazide combination.

ACE inhibitors (eg, captopril)

The risk of acute renal dysfunction may be increased. Monitor renal function, especially in elderly patients and patients with renal impairment.

Amphotericin B, corticosteroids, corticotropin

Electrolyte depletion may be intensified, particularly hypokalemia. Laboratory monitoring of serum potassium is warranted.

Anesthetics, general (eg, thiopental)

Hypotension may be exaggerated. Adjust dosage as needed.

Anticholinesterases (eg, neostigmine)

The risk of severe and prolonged bradycardia may be increased. Use with caution.

Anticoagulants, oral

Anticoagulant effects may be decreased. Adjust treatment as needed.

Antigout agents (eg, probenecid)

Because thiazide diuretics may raise blood uric acid levels, dosage adjustment of antigout agents may be necessary.

Antihypertensive agents

Additive or potentiation of hypotensive effects. Closely monitor BP.

Antineoplastic agents (eg, cyclophosphamide)

Thiazides may prolong antineoplastic-induced myelosuppression. Use with caution.

Bile acid sequestrants (eg, cholestyramine, colestipol)

Bendroflumethiazide absorption may be delayed or decreased. Separate the administration times by at least 4 h. A higher dose of nadolol/bendroflumethiazide may be needed.

Bupivacaine

Plasma concentrations and pharmacologic effects of bupivacaine may be increased by nadolol. Reduce dose of bupivacaine as needed.

Calcium channel blockers (eg, diltiazem, nifedipine, verapamil)

Pharmacologic effects may be increased. Hypotension, bradycardia, cardiac failure, and life-threatening cardiac conduction abnormalities may result. Monitor CV status closely and adjust dosage as needed.

Calcium salts

Hypercalcemia and possible calcium toxicity may occur because of decreased calcium excretion. Monitor calcium levels and adjust the dose as needed.

Carbonic anhydrase inhibitors (eg, acetazolamide)

Nadolol may exacerbate carbonic anhydrase inhibitor–induced acidosis, especially in patients with respiratory disorders. If acidosis occurs, discontinue one or both drugs.

Catecholamine-depleting drugs (eg, reserpine)

Additive effects may occur. Monitor closely for hypotension and/or excessive bradycardia.

CNS depressants (eg, alcohol, barbiturates, narcotics)

Potentiation of orthostatic hypotension may occur. Monitor BP.

Clonidine

Rebound hypertension associated with abrupt withdrawal of clonidine may be more severe in patients taking nadolol. Paradoxical hypertension may also occur. Avoid abrupt withdrawal of clonidine. Discontinue either agent gradually; preferably, discontinue the nadolol first.

Diazoxide

The pharmacologic effects of both drugs may be increased. Hyperglycemia, hyperuricemia, and hypotension may occur. Closely monitor BP, blood and urine glucose, and serum uric acid. If coadministration cannot be avoided, a decreased dosage of one or both agents may be required.

Digitalis glycosides (eg, digoxin)

The risk of bradycardia is increased because nadolol and digitalis both slow AV conduction and decrease heart rate. Monitor cardiac function and heart rate. In addition, thiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias. Measure plasma concentrations of potassium and magnesium; supplement low levels.

Dofetilide

Dofetilide plasma concentrations may be increased and/or hypokalemia may occur. Prolongation of the QT interval may occur, increasing the risk of torsades de pointes. Coadministration is contraindicated.

Epinephrine

Increasing vascular resistance leads to an initial hypertensive episode followed by bradycardia due to the unopposed alpha-adrenergic effects of epinephrine. Epinephrine resistance may also occur while treating allergic reactions. Avoid coadministration.

Ergot alkaloids (eg, ergotamine)

Peripheral vasoconstriction with possible ischemia and cyanosis of the extremities may occur.

Fingolimod

Fingolimod-related bradycardia may be increased. Monitor closely, especially during initiation of fingolimod therapy.

Flecainide

Pharmacologic effects of both drugs may be increased. Severe bradycardia and cardiac arrest may occur. Use with caution and closely monitor.

Glucagon

The hyperglycemic effect may be blunted. Consider administering glucose for a hypoglycemic episode in a patient on nadolol therapy.

Hypoglycemic agents, oral (eg, meglitinides, sulfonylureas)

The effect of oral hypoglycemic agents may be increased or decreased by nadolol. Nadolol also masks symptoms of hypoglycemia. In addition, the hypoglycemic effects of sulfonylureas may be decreased by thiazides. Monitor blood glucose and adjust the hypoglycemic dose as needed.

Insulin

Nadolol prolongs and masks symptoms of hypoglycemia. Monitor blood glucose and adjust the insulin dose as needed. In contrast, thiazides may increase fasting blood glucose and decrease insulin secretion. The effect of insulin may be decreased. Monitor blood glucose and adjust the insulin dose as needed. Consider a cardioselective beta-blocker.

Lidocaine

Elevated lidocaine plasma concentrations with toxicity may occur. Monitor lidocaine plasma concentrations and the patient for evidence of toxicity.

Lithium

Lithium Cl may be decreased, increasing lithium concentrations and the risk of lithium toxicity. Lithium generally should not be given with diuretics. If concurrent use cannot be avoided, monitor serum lithium levels and adjust the dose accordingly. Coadministration of lithium and nadolol may cause bradycardia.

Loop diuretics (eg, furosemide)

Bendroflumethiazide and furosemide have synergistic effects that may result in profound diuresis and serious electrolyte abnormalities. Monitor for dehydration and electrolyte abnormalities during combined therapy. Titrate dosage with small or intermittent doses.

MAOIs (eg, phenelzine)

Hypotensive effects may be enhanced with thiazides. Bradycardia may occur or worsen during coadministration with nadolol. Adjust the dosage of one or both agents.

Mefloquine

Coadministration may cause CV toxicity, including ECG abnormalities such as AV block or QT interval prolongation. Consider an alternative to mefloquine. If coadministration cannot be avoided, close clinical and ECG monitoring is needed.

Methenamine

Possible decreased effectiveness due to alkalinization of the urine.

Methyldopa

Paradoxical hypertension may be a rare complication of treatment with methyldopa and nonselective beta-adrenergic blocking agents.

Nondepolarizing muscle relaxants (eg, tubocurarine)

Possible increase in responsiveness to the muscle relaxant due to diuretic-induced hypokalemia. If hypokalemia cannot be corrected, a lower dosage of nondepolarizing muscle relaxants may be needed.

NSAIDs (eg, ibuprofen, indomethacin)

The antihypertensive effects of nadolol may be reduced and the diuretic, natriuretic, and antihypertensive effects of bendroflumethiazide may be reduced. Rarely, coadministration may also result in deterioration of renal function, including acute renal failure. Monitor BP, renal function, and the diuretic response.

Pressor amines (eg, norepinephrine)

Response to pressor amines may be decreased. Use with caution. If possible, stop bendroflumethiazide 1 wk before surgery.

Quinazolines (eg, prazosin)

Coadministration may enhance the severity and duration of postural hypotension.

Sympathomimetics (eg, albuterol, salmeterol)

Pharmacologic effects of sympathomimetics may be decreased. If possible, avoid concurrent use. If coadministration cannot be avoided, consider a cardioselective beta-blocker.

Theophylline

The bronchodilating effect of theophyllines may be impaired. Avoid coadministration. Consider cardioselective beta-blockers.

Tretinoin

The risk of phototoxicity may be increased if these agents are coadministered. Avoid coadministration.

Laboratory Test Interactions

Thiazides may decrease serum protein-bound iodine levels without signs of thyroid disturbance. Thiazides should be discontinued before carrying out tests for parathyroid function. Bendroflumethiazide may produce false-negative results with the phentolamine and tyramine tests, may interfere with the phenolsulfonphthalein test due to decreased excretion, and may cause interference of serum electrolyte levels and blood and urine glucose levels.

Adverse Reactions

Cardiovascular

Bradycardia, peripheral vascular insufficiency (2%); cardiac failure, hypotension, rhythm/conduction disturbances (1%); first- and third-degree heart block; orthostatic hypotension.

CNS

Dizziness, fatigue (2%); change in behavior, paresthesia, sedation (1%); headache, slurred speech (up to 1%); restlessness; vertigo.

Dermatologic

Pruritus, rash, sweating (up to 1%); ecchymosis; exfoliative dermatitis; photosensitivity; purpura; urticaria.

EENT

Blurred vision, tinnitus (up to 1%); xanthopsia.

GI

Abdominal discomfort, anorexia, bloating, constipation, diarrhea, flatulence, indigestion, nausea, vomiting (up to 1%); cramping; gastric irritation; pancreatitis; sialadenitis.

Genitourinary

Impotence or decreased libido (up to 1%); allergic glomerulonephritis; glycosuria.

Hematologic

Agranulocytosis; aplastic anemia; hemolytic anemia; leukopenia; thrombocytopenia.

Hepatic

Hepatitis; jaundice (intrahepatic cholestatic jaundice).

Hypersensitivity

Anaphylactic reactions; fever; necrotizing angiitis (cutaneous vasculitis, vasculitis); respiratory distress, including pneumonitis.

Metabolic

Hyperglycemia; hyperuricemia.

Respiratory

Cough, nasal stuffiness (up to 1%).

Miscellaneous

Dry mouth, eyes, or skin, facial swelling, weight gain (up to 1%); muscle spasm; weakness.

Precautions

Warnings

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, MI have occurred after abrupt discontinuation of such therapy. When discontinuing long-term nadolol administration, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 wk and carefully monitor the patient. If angina markedly worsens or acute coronary insufficiency develops, reinstitute nadolol administration promptly, at least temporarily, and take other measures appropriate for the management of unstable angina. Warn patients against interruption or discontinuation of therapy without their health care provider's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue nadolol therapy abruptly, even in patients treated only for hypertension.


Monitor

Observe patients for signs of fluid or electrolyte imbalance. Periodically determine serum electrolytes at appropriate intervals. Periodic BUN and creatinine determinations should be made, especially for elderly patients and in patients with confirmed or suspected renal insufficiencies. Monitor blood glucose in diabetic patients when a drug is started or dose is changed.


Pregnancy

Category C . Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Lactation

Excreted.

Children

Safety and efficacy not established.

Elderly

Nadolol/bendroflumethiazide is excreted by the kidneys; the risk of toxic reactions may be greater in patients with renal impairment.

Hypersensitivity

May occur in patients with or without a history of allergy or bronchial asthma.

Renal Function

Use with caution in patients with renal disease; thiazides may precipitate azotemia. Cumulative effects may develop in patients with impaired renal function. Dosage adjustment is required.

Hepatic Function

Use with caution in patients with impaired hepatic function or progressive liver disease because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Cardiac failure

Sympathetic stimulation may be a vital component supporting circulatory function in patients with CHF, and its inhibition by beta-blockade may precipitate more severe failure. Avoid beta-blockers in patients with overt CHF; however, if necessary, they can be used with caution in patients with a history of heart failure who are well compensated, usually with diuretics and digitalis. In patients without a history of heart failure, continued use of beta-blockers can, in some cases, lead to cardiac failure.

Diabetes/Hypoglycemia

Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms of acute hypoglycemia. This is especially important with labile diabetic patients. Latent diabetes may manifest during administration.

Electrolyte imbalance

Hypokalemia, hypercalcemia, hypophosphatemia, hypochloremic alkalosis, hypomagnesemia, and/or hyponatremia may occur.

Hyperuricemia

May occur, or acute gout may be precipitated.

Postsympathectomy

The antihypertensive effects of thiazide diuretics may be enhanced in postsympathectomy patients.

Respiratory effects

Patients with bronchospastic disease should generally not receive beta-blockers.

Surgery

The impaired ability of the heart to respond to reflux adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Systemic lupus erythematosus

May be activated or exacerbated.

Thyroid effects

Beta-adrenergic blockade may mask certain clinical signs (eg, 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.

Overdosage

Symptoms

Bradycardia, bronchospasm, cardiac failure, depressed cardiovascular function, electrolyte changes, GI irritation, hypotension, increased BUN, lethargy progressing to coma, respiratory depression.

Patient Information

  • Warn patients, especially those with evidence of coronary artery insufficiency, against interruption or discontinuation of therapy without their health care provider's approval.
  • Advise patients to consult their health care provider at the first sign or symptom of impending cardiac failure.
  • Caution patients that light-headedness can occur, especially during the first days of therapy, and advise them to report it to their health care provider.
  • Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to excessive fall in BP, resulting in light-headedness or fainting.
  • Instruct diabetic patients to monitor blood glucose more frequently when nadolol/bendroflumethiazide is started or the dose is changed, and to inform their health care provider of significant changes.
  • Caution patients to avoid unnecessary exposure to UV light (sunlight, tanning booths), use sunscreen, and wear protective clothing when exposed to UV light to avoid a photosensitivity reaction.
  • Instruct patients to stop taking nadolol/bendroflumethiazide and immediately report any of the following symptoms to their health care provider: fainting or swelling of the face, lips, eyelids, or tongue.
  • Caution patients to not take any prescription or OTC medications, potassium salt substitutes, or potassium dietary supplements unless advised by their health care provider.

Copyright © 2009 Wolters Kluwer Health.

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