f 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.

lar 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. 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 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. major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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 beta1-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. 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.

iatric experience with bisoprolol fumarate.

within the recommended dosage range (5 mg to 20 mg). of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue and sinusitis appear to be dose related. body system/adverse experience all adverse experiences (% a ) bisoprolol fumarate placebo (n = 132) % 5 mg to 20 mg (n = 273) % 2.5 mg to 40 mg (n = 404) % skin increased sweating 1.5 0.7 1.0 musculoskeletal arthralgia 2.3 2.2 2.7 central nervous system dizziness 3.8 2.9 3.5 headache 11.4 8.8 10.9 hypoaesthesia 0.8 1.1 1.5 autonomic nervous system dry mouth 1.5 0.7 1.3 heart rate/rhythm bradycardia 0 0.4 0.5 psychiatric vivid dreams 0 0 0 insomnia 2.3 1.5 2.5 depression 0.8 0 0.2 gastrointestinal diarrhea 1.5 2.6 3.5 nausea 1.5 1.5 2.2 vomiting 0 1.1 1.5 respiratory bronchospasm 0 0 0 cough 4.5 2.6 2.5 dyspnea 0.8 1.1 1.5 pharyngitis 2.3 2.2 2.2 rhinitis 3.0 2.9 4.0 sinusitis 1.5 2.2 2.2 uri 3.8 4.8 5.0 body as a whole asthenia 0 0.4 1.5 chest pain 0.8 1.1 1.5 fatigue 1.5 6.6 8.2 edema (peripheral) 3.8 3.7 3.0 a percentage of patients with event. the following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in post-marketing experience (in italics): central nervous system: dizziness, unsteadiness , vertigo , syncope, headache, paresthesia, hypoaesthesia, hyperesthesia, somnolence, sleep disturbances , anxiety/restlessness, decreased concentration/memory. autonomic nervous system: dry mouth. cardiovascular: bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion. psychiatric: vivid dreams, insomnia, depression. gastrointestinal: gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer. musculoskeletal: muscle/joint pain, arthralgia , back/neck pain, muscle cramps, twitching/tremor. skin: rash, acne, eczema, psoriasis , skin irritation, pruritus, flushing, sweating, alopecia, dermatitis , angioedema , exfoliative dermatitis , cutaneous vasculitis. special senses: visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing , earache, taste abnormalities. metabolic: gout. respiratory: asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, uri. genitourinary: decreased libido/impotence, peyronie's disease , cystitis, renal colic, polyuria. hematologic: purpura. general: fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema. in addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of bisoprolol fumarate tablets: central nervous system: reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium. allergic: fever, combined with aching and sore throat, laryngospasm, respiratory distress. hematologic: agranulocytosis, thrombocytopenia, thrombocytopenic purpura. gastrointestinal: mesenteric arterial thrombosis, ischemic colitis. miscellaneous: the oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive foreign marketing experience.

f 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.

n 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. pharmacodynamics 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. 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 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 (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 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.

f 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.

8 10.7 drug effect* - 2.2 9.1 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.