BISOPROLOL- bisoprolol fumarate tablet, film coated
BISOPROLOL FUMARATE TABLETS
Bisoprolol fumarate, USP is a synthetic, beta1-selective (cardio-selective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-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 (C18H31NO4)2•C4H4O4 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.
Bisoprolol fumarate is available as 5 mg or 10 mg for oral administration. Inactive ingredients include carnauba wax, colloidal silicon dioxide, corn starch, crospovidone, dibasic calcium phosphate, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide, triacetin. The 5 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake.
Meets USP Dissolution Test 2.
Bisoprolol fumarate is a beta1 -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 (≥ 20 mg) bisoprolol fumarate also inhibits beta2 -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 to 4 hours of dosing with 5 mg 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 2-fold intersubject variation in peak plasma levels. The plasma elimination half-life is 9 to 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 mg 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 3-fold compared to healthy subjects.
In patients with cirrhosis of the liver, the elimination of 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 bisoprolol fumarate tablets 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 bisoprolol fumarate tablets 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:
1) Decreased cardiac output,
2) Inhibition of renin release by the kidneys,
3) Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
In normal volunteers, bisoprolol fumarate tablets therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 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 bisoprolol fumarate tablets significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.
Beta1 -selectivity of bisoprolol fumarate tablets has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta2 -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 bisoprolol fumarate tablets ranged from 5 mg to 60 mg, atenolol from 50 mg to 200 mg, metoprolol from 100 mg to 200 mg, and propranolol from 40 mg to 80 mg. In some studies, slight, asymptomatic increases in airways 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 also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.
Bisoprolol fumarate tablets 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.
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.
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.
| Sitting Systolic/Diastolic Pressure (BP) and Heart Rate (HR) |
Mean Decrease (Δ) After 3 to 4 Weeks
|Study A||Bisoprolol Fumarate|
|Placebo||5 mg||10 mg||20 mg|
|Total ΔBP (mm Hg)||5.4/3.2||10.4/8.0||11.2/10.9||12.8/11.9|
|Total ΔHR (bpm)||0.5||7.2||8.7||11.3|
|Study B||Bisoprolol Fumarate|
|Placebo||2.5 mg||10 mg|
|Total ΔBP (mm Hg)||3.0/3.7||7.6/8.1||13.5/11.2|
|Total ΔHR (bpm)||1.6||3.8||10.7|
a Observed total change from baseline minus placebo.
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 2 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.
Bisoprolol Indications and Usage
Bisoprolol fumarate tablets are indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.
Bisoprolol fumarate tablets are contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block and marked sinus bradycardia.
Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously.
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 fumarate tablets should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.
Exacerbation 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 fumarate tablets over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol fumarate tablets therapy should be reinstituted, at least temporarily.
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