Zebeta Information
Zebeta (Bisoprolol fumarate) Description
Zebeta (Bisoprolol fumarate) is a synthetic, beta-selective (cardioselective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-1-[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol()-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 empirical formula is (CHNO)•CHO and its structure is:
Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and chloroform.
Zebeta (Bisoprolol fumarate) is available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include Colloidal Silicon Dioxide, Corn Starch, Crospovidone, Dibasic Calcium Phosphate, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80, and Titanium Dioxide. The 5 mg tablets also contain Red and Yellow Iron Oxide.
Zebeta (Bisoprolol fumarate) Clinical Pharmacology
Zebeta (Bisoprolol fumarate) is a beta-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. Cardioselectivity is not absolute, however, and at higher doses ( 20mg) bisoprolol fumarate also inhibits beta-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity it is therefore important to use the lowest effective dose.
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with bisoprolol fumarate results in less than twofold intersubject variation in peak plasma levels. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population. Steady state is attained within 5 days of 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 first order kinetics and once daily dosing. Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing 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. Bisoprolol fumarate 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 cirrhosis of the liver, the elimination of Zebeta (Bisoprolol fumarate) is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.
The most prominent effect of Zebeta (Bisoprolol fumarate) is the negative chronotropic effect, resulting in 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.
Findings in short-term clinical hemodynamics studies with Zebeta (Bisoprolol fumarate) are similar to those observed with other beta-blocking agents.
The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:
In normal volunteers, Zebeta (Bisoprolol fumarate) therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that Zebeta (Bisoprolol fumarate) significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.
Beta-selectivity of Zebeta (Bisoprolol fumarate) has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta-adrenoceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of Zebeta (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 airways resistance (AWR) and decreases in forced expiratory volume (FEV) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.
Zebeta (Bisoprolol fumarate) had minimal effect on serum lipids during antihypertensive studies. In U.S. placebo-controlled trials, changes in total cholesterol averaged +0.8% for bisoprolol fumarate-treated patients, and +0.7% for placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated patients, and +17% for placebo.
Zebeta (Bisoprolol fumarate) has also been given concomitantly with thiazide diuretics. Even very low doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in lowering blood pressure in patients with mild-to-moderate hypertension.
Zebeta (Bisoprolol fumarate) Clinical Studies
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 pressures at baseline were approximately 150/100 mm Hg, and mean heart rate was 76 bpm. Drug effect is calculated by subtracting the placebo effect from the overall change in blood pressure and heart rate.
Blood pressure responses were seen within one week of treatment and changed little thereafter. They were sustained for 12 weeks and for over a year in studies of longer duration. Blood pressure returned to baseline when bisoprolol fumarate was tapered over two weeks in a long-term study.
Overall, significantly greater blood pressure reductions were observed on bisoprolol fumarate than on placebo regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.
Zebeta (Bisoprolol fumarate) Indications And Usage
Zebeta (Bisoprolol fumarate) is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.
Zebeta (Bisoprolol fumarate) Contraindications
Zebeta (Bisoprolol fumarate) is contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.
Zebeta (Bisoprolol fumarate) Warnings
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta-selectivity, however, Zebeta (Bisoprolol fumarate) may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta-selectivity is not absolute, the lowest possible dose of Zebeta (Bisoprolol fumarate) should be used, with therapy starting at 2.5 mg. A beta agonist (bronchodilator) should be made available
Zebeta (Bisoprolol fumarate) Precautions
Zebeta (Bisoprolol fumarate) should not be combined with other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-adrenergic blocking action of Zebeta (Bisoprolol fumarate) may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Zebeta (Bisoprolol fumarate) be discontinued for several days before the withdrawal of clonidine.
Zebeta (Bisoprolol fumarate) should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Concurrent use of rifampin increases the metabolic clearance of Zebeta (Bisoprolol fumarate) , resulting in a shortened elimination half-life of Zebeta (Bisoprolol fumarate) . However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics, and cimetidine. There was no effect of Zebeta (Bisoprolol fumarate) on prothrombin time in patients on stable doses of warfarin.
Risk of Anaphylactic Reaction:
Patients, especially those with coronary artery disease, should be warned about discontinuing use of Zebeta (Bisoprolol fumarate) without a physician’s supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of congestive heart failure or excessive bradycardia.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be used with caution.
Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness.
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these and assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively.
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Zebeta (Bisoprolol fumarate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Zebeta (Bisoprolol fumarate) has been used in elderly patients with hypertension. Response rates and mean decreases in systolic and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies. Although no dose response study was conducted in elderly patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol fumarate.
Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.
Zebeta (Bisoprolol fumarate) Adverse Reactions
Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.
In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5-20 mg of bisoprolol fumarate; 132 received placebo.
Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.
The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5-40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5-20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.
The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics):
Zebeta (Bisoprolol fumarate) Overdosage
The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.
In general, if overdose occurs, Zebeta (Bisoprolol fumarate) therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:
Zebeta (Bisoprolol fumarate) Dosage And Administration
The dose of Zebeta (Bisoprolol fumarate) must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose (see Bronchospastic Disease in ). If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily.
Zebeta (Bisoprolol fumarate) How Supplied
The 5 mg tablet is pink, heart-shaped, biconvex, film-coated, vertically scored in half on both sides, with an engraved stylized b/stylized b on one side and 6/0 on the reverse side, supplied as follows:
The 10 mg tablet is white, heart-shaped, biconvex, film-coated, with an engraved stylized b on one side and 61 on the reverse side, supplied as follows:
Zebeta (Bisoprolol fumarate)
Zebeta (Bisoprolol fumarate) Principal Display Panel - Mg
NDC 51285-060-01
Zebeta (Bisoprolol fumarate) (bisoprolol fumarate)Tablets
5 mg
30 TabletsUnit-of-use
Rx only
DOSAGE: For complete directions for use, see accompanying circular.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture.
Zebeta (Bisoprolol fumarate) Principal Display Panel - Mg
NDC 51285-061-01
Zebeta (Bisoprolol fumarate) (bisoprolol fumarate)Tablets
10mg
30 TabletsUnit-of-use
Rx only
DOSAGE: For complete directions for use, see accompanying circular.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture.
