Bisoprolol Fumarate Hydrochlorothiazide: Package Insert and Label Information

BISOPROLOL FUMARATE HYDROCHLOROTHIAZIDE- bisoprolol fumarate and hydrochlorothiazide tablet, film coated
Watson Laboratories, Inc.

DESCRIPTION

Bisoprolol fumarate and hydrochlorothiazide is indicated for the treatment of hypertension. It combines two antihypertensive agents in a once-daily dosage: a synthetic beta1 -selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a benzothiadiazine diuretic (hydrochlorothiazide).

Bisoprolol fumarate is chemically described as (±)-1-[4-[[-2-(1-methylethoxy)ethoxy]methyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol(E) -2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its molecular formula is (C18 H31 NO4 )2 •C4 H4 O4 and it has a molecular weight of 766.97. Its structural formula is:

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Bisoprolol fumarate is a white crystalline powder, approximately equally hydrophilic and lipophilic, and readily soluble in water, methanol, ethanol, and chloroform.

Hydrochlorothiazide USP (HCTZ) is 6-Chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white, or practically white, practically odorless crystalline powder. It is slightly soluble in water, sparingly soluble in dilute sodiumum hydroxide solution, freely soluble in n-butylamine and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. Its molecular formula is C7 H8 CIN3 O4 S2 and it has a molecular weight of 297.73. Its structural formula is:

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Each tablet, for oral administration contains 2.5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, 5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide, or 10 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide. In addition, each tablet contains the following inactive ingredients: colloidal silicone dioxide, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The film-coating contains the following ingredients: hypromellose, lactose monohydrate (2.5 mg/6.25 mg and 5 mg/6.25 mg only), polyethylene glycol (10 mg/6.25 mg only), polydextrose (10 mg/6.25 mg only), purified stearic acid (5 mg/6.25 mg only), synthetic red iron oxide (5 mg/6.25 mg only), synthetic yellow iron oxide (2.5 mg/6.25 mg and 5 mg/6.25 mg only), titanium dioxide, and triacetin.

CLINICAL PHARMACOLOGY

Bisoprolol and HCTZ have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive; HCTZ 6.25 mg significantly increases the antihypertensive effect of bisoprolol. The incidence of hypokalemia with the bisoprolol fumarate and HCTZ 6.25 mg combination (B/H) is significantly lower than with HCTZ 25 mg. In clinical trials of bisoprolol and hydrochlorothiazide, mean changes in serum potassium for patients treated with bisoprolol fumarate and hydrochlorothiazide 2.5/6.25 mg, or 5/6.25 mg or 10/6.25 mg or placebo were less than ± 0.1 mEq/L. Mean changes in serum potassium for patients treated with any dose of bisoprolol in combination with HCTZ 25 mg ranged from -0.1 to -0.3 mEq/L.

Bisoprolol is a beta1 -selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses (≥20 mg) bisoprolol also inhibits beta2 -adrenoreceptors located in bronchial and vascular musculature. To retain relative selectivity, it is important to use the lowest effective dose.

Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanisms of electrolyte reabsorption and increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

Pharmacokinetics and Metabolism

Bisoprolol and hydrochlorothiazide

In healthy volunteers, both bisoprolol and hydrochlorothiazide are well absorbed following oral administration of bisoprolol and hydrochlorothiazide. No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether bisoprolol and hydrochlorothiazide is taken with or without food. Mean peak bisoprolol plasma concentrations of about 9.0 ng/mL, 19 ng/mL and 36 ng/mL occur approximately 3 hours after the administration of the 2.5 mg/6.25 mg, 5 mg/6.25 mg and 10 mg/6.25 mg combination tablets, respectively. Mean peak plasma hydrochlorothiazide concentrations of 30 ng/mL occur approximately 2.5 hours following administration of the combination. Dose proportional increases in plasma bisoprolol concentrations are observed between the 2.5 and 5, as well as between the 5 and 10 mg doses. The elimination T1/2 of bisoprolol ranges from 7 to 15 hours and of hydrochlorothiazide ranges from 4 to 10 hours. The percent of dose excreted unchanged in urine is about 55% for bisoprolol and about 60% for hydrochlorothiazide.

Bisoprolol

The absolute bioavailability after a 10 mg oral dose of bisoprolol is about 80%. The first pass metabolism of bisoprolol is about 20%.

The pharmacokinetic profile of bisoprolol has been examined following single doses and at steady state. Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of dosing with 2.5 to 20 mg, and mean peak values range from 9.0 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with bisoprolol results in less than twofold intersubject variation in peak plasma concentrations. Plasma concentrations are proportional to the administered dose in the range of 2.5 to 20 mg. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part because of decreased renal function. Steady state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the half-life and once-daily dosing. Bisoprolol is eliminated equally by renal and nonrenal pathways with about 50% of the dose appearing unchanged in the urine and the remainder in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. The pharmacokinetic characteristics of the two enantiomers are similar. Bisoprolol is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).

In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.

In patients with liver cirrhosis, the rate of elimination of bisoprolol is more variable and significantly slower than that in healthy subjects, with a plasma half-life ranging from 8 to 22 hours.

In elderly subjects, mean plasma concentrations at steady state are increased, in part attributed to lower creatinine clearance. However, no significant differences in the degree of bisoprolol accumulation is found between young and elderly populations.

Hydrochlorothiazide

Hydrochlorothiazide is well absorbed (65%-75%) following oral administration. Absorption of hydrochlorothiazide is reduced in patients with congestive heart failure.

Peak plasma concentrations are observed within 1-5 hours of dosing, and range from 70-490 ng/mL following oral doses of 12.5 mg to 100 mg. Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide are 1.6-1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6-15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 mg to 100 mg, 55%-77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. Plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged in patients with renal disease.

Pharmacodynamics

Bisoprolol

Findings in clinical hemodynamics studies with bisoprolol are similar to those observed with other beta-blockers. The most prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

In normal volunteers, bisoprolol therapy resulted in a reduction of exercise-and isoproterenol-induced tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater.

In controlled clinical trials, bisoprolol given as a single daily dose has been shown to be an effective antihypertensive agent when used alone or concomitantly with thiazide diuretics (see CLINICAL STUDIES).

The mechanism of bisoprolol’s antihypertensive effect has not been completely established. Factors that may be involved include:

  1. Decreased cardiac output,

  2. Inhibition of renin release by the kidneys,

  3. Diminution of tonic sympathetic outflow from vasomotor centers in the brain.

Beta1 -selectively of bisoprolol has been demonstrated in both animals and human studies. No effects at therapeutic doses on beta2 -adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV1 ) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.

Electrophysiology studies in man have demonstrated that bisoprolol significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.

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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