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 should be considered.
In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.
Abrupt Cessation of Therapy 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 over approximately one week with the patient under careful observation.
If withdrawal symptoms occur, BISOPROLOL FUMARATE 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 DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS.
Because of its relative beta 1 -selectivity, however, 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 1 -selectivity is not absolute, the lowest possible dose of BISOPROLOL FUMARATE should be used, with therapy starting at 2.5 mg.
A beta 2 agonist (bronchodilator) should be made available.
Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risk of general anesthesia and surgical procedures.
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 its beta 1 -selectivity, this is less likely with BISOPROLOL FUMARATE.
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.
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.
Drug Interactions 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 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 BISOPROLOL FUMARATE be discontinued for several days before the withdrawal of clonidine.
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 BISOPROLOL FUMARATE, resulting in a shortened elimination half-life of 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 BISOPROLOL FUMARATE on prothrombin time in patients on stable doses of warfarin.
Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
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 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.
Hypotension IV fluids and vasopressors should be administered.
Intravenous glucagon may be useful.
Heart Block (second or third degree) Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
Congestive Heart Failure Initiate conventional therapy (i.e., digitalis, diuretics, inotropic agents, vasodilating agents).
Bronchospasm Administer bronchodilator therapy such as isoproterenol and/or aminophylline.
Hypoglycemia Administer IV glucose.
BISOPROLOL FUMARATE USP is 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.
The S(-) enantiomer is responsible for most of the beta-blocking activity.
Its molecular formula is (C 18 H 31 NO 4 ) 2 •C 4 H 4 O 4 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 TABLETS USP are available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include Colloidal Silicon Dioxide, Corn Starch (Pregelatinized), 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.
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 a Observed Total change from baseline minus placebo.
n = 61 61 61 61 Total Δ BP (mm Hg) 5.4/3.2 10.4/8.0 11.2/10.9 12.8/11.9 Drug Effect a – 5.0/4.8 5.8/7.7 7.4/8.7 Total Δ HR (bpm) 0.5 7.2 8.7 11.3 Drug Effect a – 6.7 8.2 10.8 Study B Bisoprolol Fumarate Placebo 2.5 mg 10 mg n = 56 59 62 Total Δ BP (mm Hg) 3.0/3.7 7.6/8.1 13.5/11.2 Drug Effect a – 4.6/4.4 10.5/7.5 Total Δ HR (bpm) 1.6 3.8 10.7 Drug Effect a – 2.2 9.1 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.
BISOPROLOL FUMARATE is supplied as 5 mg and 10 mg tablets.
The 5 mg tablet is pink colored, biconvex, round, film coated tablet debossed with UL on one side and scored on the other side with 5 debossed on either side of the score.
Bottles of 30: NDC 68788-6775-3 Bottles of 60: NDC 68788-6775-6 Bottles of 90: NDC 68788-6775-9 Bottles of 100: NDC 68788-6775-1 Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature].
Protect from moisture.
Dispense in tight, light-resistant containers.
Please address medical inquiries to Unichem’s toll free # 1-866-562-4616.
Geriatric Use 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.
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.
INDICATIONS AND USAGE
BISOPROLOL FUMARATE is indicated in the management of hypertension.
It may be used alone or in combination with other antihypertensive agents.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Nursing Mothers 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.
INFORMATION FOR PATIENTS
Information for Patients Patients, especially those with coronary artery disease, should be warned about discontinuing use of 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.
DOSAGE AND ADMINISTRATION
The dose of 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 WARNINGS ).
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.
Patients with Renal or Hepatic Impairment 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.
Geriatric Patients It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction (see above and Geriatric Use in PRECAUTIONS ) .
Pediatric Patients There is no pediatric experience with BISOPROLOL FUMARATE.