Pronunciation: BIS-oh-PROE-lol/HYE-droe-KLOR-oh-THYE-a-zide
Class: Antihypertensive

Trade Names

Ziac
- Tablets, oral bisoprolol 2.5 mg/hydrochlorothiazide 6.25 mg
- Tablets, oral bisoprolol 5 mg/hydrochlorothiazide 6.25 mg
- Tablets, oral bisoprolol 10 mg/hydrochlorothiazide 6.25 mg

Pharmacology

Bisoprolol

Blocks beta receptors, primarily affecting heart (slows rate), vascular system (decreases BP), and, to a lesser extent, lungs (reduced function).

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Hydrochlorothiazide

Increases chloride, sodium, and water excretion by interfering with transport of sodium ions across renal tubular epithelium.

Indications and Usage

For the management of hypertension.

Unlabeled Uses

Pediatric hypertension.

Contraindications

Cardiogenic shock; overt cardiac failure; second- or third-degree AV block; marked sinus bradycardia; anuria; hypersensitivity to either component of product or other sulfonamide derivatives.

Dosage and Administration

Adults

PO Bisoprolol 2.5 mg/hydrochlorothiazide 6.25 mg daily initially. Increase the dose in 14-day intervals until optimal response is obtained (max, bisoprolol 20 mg/hydrochlorothiazide 12.5 mg).

General Advice

• Administer once daily with or without food.
• When discontinuing therapy, gradually withdraw therapy over a period of about 2 weeks.

Storage/Stability

Store at 68° to 77°F.

Drug Interactions

ACE inhibitors (eg, captopril)

Coadministration may increase the risk of acute renal dysfunction. Monitor renal function, especially in elderly patients and in patients with impaired renal function.

Alcohol, barbiturates, narcotics

Potentiation of orthostatic hypotension may occur. Closely monitor serum potassium.

Amantadine

Coadministration may increase the incidence of toxic effects of amantadine.

Antihypertensives (eg, reserpine, guanethidine, nifedipine, verapamil)

Additive or potentiation of hypotension effects may occur. Coadministration may result in hypotension, bradycardia, cardiac failure, and life-threatening cardiac conduction abnormalities. Closely monitor BP. Do not coadminister with other beta-blocking agents.

Antineoplastic agents (eg, cyclophosphamide)

Hydrochlorothiazide may prolong antineoplastic-induced myelosuppression. If coadministration cannot be avoided, use with caution.

Bupivacaine

Plasma concentrations and pharmacologic effects of bupivacaine may be increased with concurrent use. Additionally, the cardiotoxicity of bupivacaine may be increased. Dosage reduction of bupivacaine may be needed during coadministration.

Cholestyramine, colestipol resins

Hydrochlorothiazide absorption may be impaired. Single doses of cholestyramine or colestipol resins bind hydrochlorothiazide, reducing GI absorption up to 85% and 43%, respectively. Separate the administration times by as much as possible, and by at least 4 hours. Adjust diuretic dose as needed.

Cimetidine

Pharmacologic effects of bisoprolol may be increased (eg, bradycardia, hypotension). Dosage reduction of bisoprolol/hydrochlorothiazide may be needed. Consider alternative therapy.

Clonidine

Coadministration may cause paradoxical hypertension. In addition, withdrawal hypertension may be more severe. Avoid abrupt discontinuation of clonidine. Withdraw bisoprolol/hydrochlorothiazide several days before the gradual withdrawal of clonidine to lessen the risk of rebound hypertension.

Corticosteroids, corticotropin

Electrolyte depletion may be intensified, particularly hypokalemia. Closely monitor serum potassium.

COX-2 inhibitors (eg, celecoxib), NSAIDs (eg, ibuprofen, indomethacin, ketorolac [nasal])

The diuretic, natriuretic, and antihypertensive effects of bisoprolol/hydrochlorothiazide may be reduced. In addition, concomitant use may further deteriorate renal function, especially in volume-depleted patients or patients with renal impairment. Monitor BP and renal function.

Diazoxide

The pharmacologic effects of both drugs may be increased. Hyperglycemia, hyperuricemia, and hypotension may occur. Closely monitor blood pressure, blood glucose, and serum uric acid.

Digoxin

Hydrochlorothiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias. Measure plasma concentrations of potassium and magnesium; supplement low levels. Prevent further losses with dietary management.

Dofetilide

Plasma concentrations of dofetilide 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.

Flecainide

Pharmacologic effects of bisoprolol/hydrochlorothiazide and flecainide may be increased. Severe bradycardia and cardiac arrest may occur with coadministration. Use with caution.

Hypoglycemic agents (eg, sulfonylureas)

Hydrochlorothiazide may increase fasting blood glucose and decrease the hypoglycemic action of sulfonylureas. Closely monitor clinical and laboratory findings and adjust therapy as needed.

Insulin

Insulin requirements may increase or decrease, or remain unchanged. Monitor blood glucose and adjust the insulin dose as needed.

Loop diuretics (eg, furosemide)

Loop diuretics and hydrochlorothiazide have synergistic effects that may result in profound diuresis and electrolyte abnormalities. Monitor fluid status and electrolyte abnormalities.

Mefloquine

Coadministration may cause CV toxicity, including ECG abnormalities, such as AV block or QT-interval prolongation. Consider alternatives to mefloquine.

Mibefradil

Coadministration may increase the CV toxicity, including significant lowering of heart rate and suppression of sinoatrial node activity.

Nondepolarizing muscle relaxants (eg, tubocurarine)

Possible increased 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.

Pressor amines (eg, norepinephrine)

Response to pressor amines may be decreased. Use with caution.

Rifamycins (eg, rifampin)

The pharmacologic effects of bisoprolol may be reduced. Monitor BP.

Tretinoin

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

Laboratory Test Interactions

Hydrochlorothiazide may decrease serum protein-bound iodine levels without signs of thyroid disturbance. Interrupt therapy for a few days before carrying out tests of parathyroid function.

Adverse Reactions

Cardiovascular

Chest pain (2%); arrhythmia, bradycardia, peripheral ischemia (1%).

CNS

Dizziness, fatigue, headache (5%); impotence, insomnia, somnolence (1%).

EENT

Rhinitis (1%).

GI

Diarrhea (4%); dyspepsia, nausea (1%).

Metabolic

Hypokalemia (1%); decreased HDL cholesterol; hyperuricemia; increased triglycerides.

Musculoskeletal

Myalgia (2%); muscle cramps (1%).

Respiratory

Cough, upper respiratory tract infection (2%).

Miscellaneous

Peripheral edema (1%).

Precautions

Monitor Correct volume and/or salt depletion before initiating therapy. Evaluate renal function and measure serum electrolytes before stating therapy and periodically thereafter. Monitor BP and pulse on a regular basis.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hypersensitivity

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

Renal Function

Cumulative effects of the thiazides may develop, precipitating azotemia.

Hepatic Function

Use with caution in patients with impaired hepatic function or progressive liver disease.

Photosensitivity

Has been reported in patients taking thiazides.

Bronchospastic disease

Avoid use in patients with bronchospastic pulmonary disease. Use with caution if therapy cannot be avoided.

Cardiac failure

Avoid use in patients with overt CHF. Use with caution if therapy cannot be avoided. Continued depression of the myocardium with beta-blockers can precipitate cardiac failure in some patients.

Diabetes and hypoglycemia

May mask symptoms of hypoglycemia, such as tachycardia. Latent diabetes may manifest during thiazide therapy.

Discontinuation

Exacerbations of angina pectoris and MI or ventricular arrhythmias may occur in patients with coronary artery disease following abrupt cessation of therapy. Taper therapy over approximately 1 week.

Electrolyte imbalance

Hyperkalemia, hypokalemia, hyponatremia, hypochloremic alkalosis, hypercalcemia, hypophosphatemia, hyperuricemia, and hypomagnesemia may occur.

Hyperuricemia

Hyperuricemia or acute gout may be precipitated.

Ophthalmic effects

Hydrochlorothiazide can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma occurring within hours to weeks of drug initiation.

Parathyroid disease

May precipitate change in the parathyroid glands in patients on prolonged therapy.

Peripheral vascular disease

Precipitation or exacerbation of symptoms of arterial insufficiency in patients with peripheral vascular disease may occur. Use with caution.

Postsympathectomy

The antihypertensive effects of hydrochlorothiazide may be enhanced in the postsympathectomy patient.

Surgery

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

Systemic lupus erythematosus

Thiazides may exacerbate or cause systemic lupus erythematosus.

Thyrotoxicosis

May mask clinical signs of hyperthyroidism (eg, tachycardia). Abrupt withdrawal may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Overdosage

Symptoms

Acute loss of fluid and electrolytes (eg, hypokalemia, hyponatremia, hypochloremia), alkalosis, anuria, bronchospasm, bradycardia, calf cramps, CHF, coma, confusion, convulsions, delirium, dizziness, fatigue, hypoglycemia, hypotension, impaired consciousness, increased BUN, lethargy, nausea, oliguria, paresthesia, polyuria, respiratory arrest, shock, tachycardia, thirst, vomiting, weakness.

Patient Information

• Warn patients, especially those with coronary artery disease, against discontinuing therapy without a health care provider's supervision. Advise patients to consult a health care provider if any difficulty in breathing occurs, or if they develop other signs or symptoms of CHF or excessive bradycardia.
• Caution patients who are subject to spontaneous hypoglycemia or diabetic patients receiving insulin or oral hypoglycemic agents that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.
• Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to excessive fall in BP, resulting in light-headedness or fainting.
• Caution patients to avoid unnecessary exposure to UV light (eg, sunlight, tanning booths), and to use sunscreen and wear protective clothing when exposed to UV light to avoid photosensitivity reaction.
• Advise patients that drug may cause drowsiness or dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Caution patients to not take any prescription or nonprescription medications or dietary supplements unless advised by health care provider.

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