Bisoprolol Fumarate Hydrochlorothiazide (Page 2 of 6)

Hydrochlorothiazide

Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased.

Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and actively persists for up to 24 hours.

CLINICAL STUDIES

In controlled clinical trials, bisoprolol fumarate/hydrochlorothiazide 6.25 mg has been shown to reduce systolic and diastolic blood pressure throughout a 24-hour period when administered once daily. The effects on systolic and diastolic blood pressure reduction of the combination of bisoprolol and hydrochlorothiazide were additive. Further, treatment effects were consistent across age groups (< 60, ≥ 60 years), racial groups (black, nonblack), and gender (male, female).

In two randomized, double-blind, placebo-controlled trials conducted in the U.S., reductions in systolic and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies mean systolic/diastolic blood pressure and heart rate at baseline were approximately 151/101 mm Hg and 77 bpm.

Sitting Systolic/Diastolic Pressure (BP) and Heart Rate (HR)Mean Decrease (Δ) After 3-4 Weeks
Study 1 Study 2
Placebo B5/H6.25 mg Placebo H6.25 mg B2.5/H6.25 mg B10/H6.25 mg
n= 75 150 56 23 28 25
a Observed mean change from baseline minus placebo
Total ΔBP(mm Hg) -2.9/-3.9 -15.8/-12.6 -3.0/-3.7 -6.6/-5.8 -14.1/-10.5 -15.3/-14.3
Drug Effecta -/- -12.9/-8.7 -/- -3.6/-2.1 -11.1/-6.8 -12.3/-10.6
Total ΔHR(bpm) -0.3 -6.9 -1.6 -0.8 -3.7 -9.8
Drug Effecta -6.6 +0.8 -2.1 -8.2

Blood pressure responses were seen within 1 week of treatment but the maximum effect was apparent after 2 to 3 weeks of treatment. Overall, significantly greater blood pressure reductions were observed on bisoprolol and hydrochlorothiazide than on placebo. Further, blood pressure reductions were significantly greater for each of the bisoprolol plus hydrochlorothiazide combinations than for either of the components used alone regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.

Bisoprolol Fumarate Hydrochlorothiazide Indications and Usage

Bisoprolol and hydrochlorothiazide is indicated in the management of hypertension.

CONTRAINDICATIONS

Bisoprolol and hydrochlorothiazide is contraindicated in patients in cardiogenic shock, overt cardiac failure (see WARNINGS), second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

WARNINGS

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive heart failure. However, in some patients with compensated cardiac failure, it may be necessary to utilize these agents. In such situations, they must be used cautiously.

Patients Without a History of Cardiac Failure

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of bisoprolol and hydrochlorothiazide should be considered. In some cases bisoprolol and hydrochlorothiazide therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation of Therapy

Exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician’s advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with bisoprolol and hydrochlorothiazide over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative beta 1 -selectively of bisoprolol fumarate, bisoprolol and hydrochlorothiazide may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta 1 -selectivity is not absolute, the lowest possible dose of bisoprolol and hydrochlorothiazide should be used. A beta 2 agonist (bronchodilator) should be made available.

Anesthesia and Major Surgery

If bisoprolol and hydrochlorothiazide treatment is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. See OVERDOSAGE for information on treatment of bradycardia and hypotension.

Diabetes and Hypoglycemia

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of the beta1 -selectivity, this is less likely with bisoprolol. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. Because of the very low dose of HCTZ employed, this may be less likely with bisoprolol and hydrochlorothiazide.

Thyrotoxicosis

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Renal Disease Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia. In subjects with creatinine clearance less than 40 mL/min, the plasma half-life of bisoprolol is increased up to threefold, as compared to healthy subjects. If progressive renal impairment becomes apparent, bisoprolol and hydrochlorothiazide should be discontinued. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

Hepatic Disease

Bisoprolol and hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid and electrolyte balance, which may precipitate hepatic coma. Also, elimination of bisoprolol is significantly slower in patients with cirrhosis than in healthy subjects. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

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