Nadolol and Bendroflumethiazide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Corzide: Nadolol 40 mg and bendroflumethiazide 5 mg [DSC], Nadolol 80 mg and bendroflumethiazide 5 mg [DSC] [scored]

Generic: Nadolol 40 mg and bendroflumethiazide 5 mg [DSC], Nadolol 80 mg and bendroflumethiazide 5 mg

Pharmacology

Mechanism of Action

Nadolol: Competitively blocks response to beta1- and beta2-adrenergic stimulation.

Bendroflumethiazide: Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Use: Labeled Indications

Hypertension: Management of hypertension (not for initial therapy)

Contraindications

Hypersensitivity to bendroflumethiazide, sulfonamide-derived drugs, or any component of the formulation; bronchial asthma; sinus bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; uncompensated cardiac failure; anuria

Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.

Dosage and Administration

Dosing: Adult

Hypertension: Oral: Note: Not for initial therapy. Dose must be individualized. Initial: Nadolol 40 mg/bendroflumethiazide 5 mg once daily. May increase to nadolol 80 mg/bendroflumethiazide 5 mg once daily based on patient response.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer without regard to meals.

Storage

Store at room temperature; avoid excessive heat.

Drug Interactions

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Allopurinol: Thiazide and Thiazide-Like Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy

Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Monitor therapy

CarBAMazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs. Consider therapy modification

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Monitor therapy

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Monitor therapy

Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Monitor therapy

Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dichlorphenamide: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Dichlorphenamide. Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Monitor therapy

Dofetilide: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Management: Although hydrochlorothiazide is specifically cited as a contraindication, the risk likely extends to all thiazide and thiazide-like diuretics and may be even greater with chlorthalidone or bendroflumethiazide. Consider alternatives when possible. Consider therapy modification

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

EPINEPHrine (Nasal): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Monitor therapy

Epinephrine (Racemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

EPINEPHrine (Systemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Fexinidazole [INT]: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Green Tea: May decrease the serum concentration of Nadolol. Management: Advise patients to minimize green tea consumption during nadolol treatment. The impact of separating nadolol doses from green tea consumption has not been investigated. Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Insulins: Beta-Blockers may enhance the hypoglycemic effect of Insulins. Monitor therapy

Ipragliflozin: May enhance the adverse/toxic effect of Thiazide and Thiazide-Like Diuretics. Specifically, the risk for intravascular volume depletion may be increased. Monitor therapy

Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Avoid combination

Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Monitor therapy

Methenamine: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Methenamine. Monitor therapy

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Monitor therapy

Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Thiazide and Thiazide-Like Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Opioids (Anilidopiperidine): May enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

OXcarbazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Promazine: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Promazine. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Consider therapy modification

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Consider therapy modification

Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

Bendroflumethiazide may produce false negative results with phentolamine and tyramine; may interfere with phenolsulfonphthalein test; may cause diagnostic interference with electrolyte levels (serum), glucose (serum, urine), and decreased PBI (serum) levels without signs of thyroid disturbance.

Adverse Reactions

See individual agents.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.
• Electrolyte disturbances: Hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia can occur with thiazides. As appropriate, correct electrolyte disturbances prior to initiation.
• Photosensitivity: Photosensitization may occur.
• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO₂NH₂). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.
• Conduction abnormality: Consider preexisting conditions such as sick sinus syndrome before initiating nadolol.
• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms (eg, diaphoresis, tachycardia). May also reduce insulin secretion in response to hyperglycemia; adjustment of antidiabetic drugs may be necessary.
• Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by thiazide diuretics.
• Heart failure (HF): Use with caution in patients with compensated heart failure and monitor for a worsening of the condition (efficacy of nadolol in HF has not been demonstrated).
• Hepatic impairment: Use with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid and electrolyte balance, which may precipitate hepatic coma.
• Hypercalcemia: Thiazides may decrease renal calcium excretion; consider avoiding use in patients with hypercalcemia.
• Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis.
• Parathyroid disease: Thiazide diuretics reduce calcium excretion; pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged use; should be discontinued prior to testing for parathyroid function.
• Peripheral vascular disease (PVD) and Raynaud disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud disease. Use with caution and monitor for progression of arterial obstruction.
• Pheochromocytoma (untreated): Adequate alpha-blockade is required prior to use of any beta-blocker.
• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustments are required. Discontinue use with progressive renal impairment. Cumulative effects of thiazides may develop, including azotemia, in patients with impaired renal function. Patients with chronic kidney disease may be at increased risk for developing acute renal failure with thiazides. Use is contraindicated in patients with anuria.
• Systemic lupus erythematosus (SLE): May cause SLE exacerbation or activation.
• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Other warnings/precautions:

• Abrupt withdrawal: [US Boxed Warning]: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.
• Appropriate use: Used as a replacement for separate dosing of components or combination when response to single agent is suboptimal; the fixed combination is not indicated for initial treatment of hypertension.
• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery. If given the morning of surgery, thiazides may render the patient volume depleted and blood pressure may be labile during general anesthesia.

Monitoring Parameters

Blood pressure, heart rate; fluid and electrolyte balance; serum glucose regularly (in patients with diabetes); renal function

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, abdominal cramps, lack of appetite, diarrhea, constipation, bloating, headache, muscle spasm, loss of strength and energy, or agitation. Have patient report immediately to prescriber signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), severe dizziness, passing out, chest pain, slow heartbeat, sensation of cold, burning or numbness feeling, vision changes, bruising, bleeding, or signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.