BONACOR

Bisoprolol fumarate tablets are a synthetic, beta 1 -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( E )-2-butenedioate (2:1) (salt).

It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture.

S(-) enantiomer is responsible for most of the beta-blocking activity.

Its empirical formula is (C 18 H 31 NO 4 ) 2 •C 4 H 4 O and its structure is: Bisoprolol fumarate, USP, 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 tablets are available as and 10 mg tablets for oral administration.

Inactive ingredients include Colloidal Silicon

Dioxide, Crospovidone, Dicalcium Phosphate Anhydrous, Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Pregelatinized Starch.

The coating materials for all strengths contain Macrogol/PEG, Polyvinyl Alcohol-part hydrolyzed, Talc, Titanium Dioxide.

The 5 mg tablets also contain Red Iron Oxide.

FDA approved dissolution test specifications differ from USP. structure.

Bisoprolol fumarate tablets are indicated in the management of hypertension.

It may be used alone or in combination with other antihypertensive agents.

Lactation General anesthesia Angor de Prinzmetal

Recent history of myocardial infarction Stenosing periphery arterial disease Asthma First degree atrial cell Chronic obstructive Bronchopneumopathy Cardiomyopathy restrictive Congenital Cardiology Diabetes Child under 15 years of age Female likely to be pregnant Pregnancy Hyperthyroidism Heart failure Coronary heart failure Hepatic impairment Renal impairment Surgical intervention Newborn exposed in utero to the medicine Phoechromocytoma Psoriasis Psoriasis, history Sports Subject to strict fasting Treatment of desensitization in progress Cardiac valvulopathy.

Bisoprolol fumarate tablets are a beta 1 -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 beta 2 -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 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 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 bisoprolol fumarate tablets 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 1-4 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.

Beta 1 -selectivity of bisoprolol fumarate tablets has been demonstrated in both animal and human studies.

No effects at therapeutic doses on beta 2 -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 to 60 mg, atenolol from to 200 mg, metoprolol from to 200 mg, and propranolol from to 80 mg. In some studies, slight, asymptomatic increases in airways resistance (AWR) and decreases in forced expiratory volume (FEV 1 ) 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 tablets have 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.

Mechanism of action

Bisoprolol is a beta-blocker with a high affinity for beta-1 receptors, without intrinsic sympathomimetic activity, or membrane stabilizing effect.

It has only a low affinity for beta-2 receptors in smooth bronchi and vessel muscles and beta-2 receptors involved in metabolic regulation.

As a result, bisoprolol generally does not alter airway resistance and has no metabolic effects related to action on beta-2 receptors.

The beta-1 selectivity of bisoprolol extends beyond therapeutic doses.

• Liver enzymes (increase) (Rare)
• Hypoglycaemia (Rare)
• Hypertriglyceridaemia (Rare)
• Antinuclear body (increase) (Rare)
• ASAT (increase)
• ALT (increase)
• Psoriasiform eruption (Very rare)
• Alopecia (Very rare)
• Psoriasis (Very rare)
• Psoriasis (aggravation) (Very rare)
• Rash
• Pruritus Coldness at the ends (Common)
• Numbness of the extremities (Common)
• Asthenia (Common)
• Fatigue (Common)
• Hepatitis (Rare)
• Hypersensitivity (Rare)
• Lupic syndrome (Exceptional)
• Angioedema Lacrymal hyposecretion (Rare)
• Conjunctivitis (Very rare)
• Vertigo (Common)
• Allergic Rhinitis (Rare)
• Hearing disorder (Rare)
• Depression (Uncommon)
• Sleep disorder (Uncommon)
• Nightmare (Rare)
• Hallucination (Rare)
• Bradycardia (Very common)
• Raynaud's syndrome (Common)
• Atrialculoventric block (Uncommon)
• Orthostatic hypotension (Uncommon)
• Hypotension (Common)
• Heart failure (aggravation) (Common)
• Intermittent clauding (aggravation) (Common)
• Syncope (Rare)
• Congestive puff Digestive disorder (Common)
• Vomiting Constipation
• Nausea Abdominal pain Diarrhoea Cramp (Uncommon)
• Muscle weakness (Uncommon)
• Arthropathy (Uncommon)
• Headache (Common)
• Bronchospasm (Uncommon)
• Erection disorder (Rare).

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, bisoprolol fumarate tablets 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: Bradycardia Administer IV atropine.

If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.

Under some circumstances, transvenous pacemaker insertion may be necessary.

IV fluids and vasopressors should be administered.

Intravenous glucagon may be useful.

Block (second or third degree) Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Initiate conventional therapy (ie, digitalis, diuretics, inotropic agents, vasodilating agents).

Administer bronchodilator therapy such as isoproterenol and/or aminophylline.

IV glucose.

Click here to enter Warnings Cardiac Failure 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.

In 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 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.

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 DISEASE

Because of its relative beta 1 -selectivity, however, bisoprolol fumarate tablets 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 fumarate tablets should be used, with therapy starting at 2.5 mg. A beta 2 agonist (bronchodilator) should be made available.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

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 its beta 1 -selectivity, this is less likely with bisoprolol fumarate tablets.

However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol fumarate should be used with caution.

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.

Bisoprolol fumarate tablets are contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.

The dose of bisoprolol fumarate tablets 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.

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.

In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration.

Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction.

There is no pediatric experience with bisoprolol fumarate tablets.

Bisoprolol fumarate tablets, USP, are supplied as 5 mg and 10 mg tablets.

The 5 mg tablet is pink color coated tablet, capsule shaped, convex scored tablets debossed with “6|6” on one side and “S” on the other side, supplied as follows: bottles of 30 (Unit-of-Use) NDC 43547-616-03 bottles of 100 NDC 43547-616-10 bottles of 500 NDC 43547-616-50 The 10 mg tablet is white color coated tablet, round shaped, convex tablets debossed with “6 7” on one side and “S” on the other side, supplied as follows: bottles of 30 (Unit-of-Use) NDC 43547-617-03 bottles of 100 NDC 43547-617-10 bottles of 500 NDC 43547-617-50 Store at 20 o C to 25 o C (68 o Fto 77 o F); excursions permitted to 15 o C to 30 o C (59 o Fto 86 o F) .

Protect from moisture.

Dispense in tight, light resistant containers.

Distributed by

Solco Healthcare US, LLC Somerset, NJ 08873, USA.

In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 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 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.

Bisoprolol fumarate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Small amounts of bisoprolol fumarate (< 2% of the dose) have been detected in the milk of lactating rats.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk caution should be exercised when bisoprolol fumarate is administered to nursing women.

Safety and effectiveness in pediatric patients have not been established.

Bisoprolol fumarate tablets have 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.