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 major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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

diatric experience with bisoprolol fumarate.

mended dosage range (5 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 (%*) bisoprolol fumarate placebo (n=132) 5-20 mg (n=273) 2.5-40 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 * percentage of patients with event the following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics): central nervous system dizziness, unsteadiness, vertigo, syncope, headache, paresthesia, hypoesthesia, 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 : 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. laboratory abnormalities in clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding. sporadic liver test abnormalities have been reported. in the u.s. controlled trials experience with bisoprolol fumarate treatment for 4 to 12 weeks, the incidence of concomitant elevations in sgot and sgpt from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. no patient had concomitant elevations greater than twice normal. in the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6 to 18 months, the incidence of one or more concomitant elevations in sgot and sgpt from 1 to 2 times normal was 6.2%. the incidence of multiple occurrences was 1.9%. for concomitant elevations in sgot and sgpt of greater than twice normal, the incidence was 1.5%. the incidence of multiple occurrences was 0.3%. in many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate. other laboratory changes included small increases in uric acid, creatinine, bun, serum potassium, glucose, and phosphorus and decreases in wbc and platelets. these were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate. as with other beta-blockers, ana conversions have also been reported on bisoprolol fumarate. about 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.

n 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 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 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 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 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 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 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 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 (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 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.b isoprolol 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. 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. 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 n= 61 61 61 61 total Δbp (mm hg) 5.4/3.2 10.4/8.0 11.2/10.9 12.8/11.9 drug effect* - 5.0/4.8 5.8/7.7 7.4/8.7 total Δhr (bpm) 0.5 7.2 8.7 11.3 drug effect* - 6.7 8.2 10.8 study b bisoprolol fumarate placebo 2.5 mg 10 mg n= 56 59 62 total Δbp (mm hg) 3.0/3.7 7.6/8.1 13.5/11.2 drug effect* - 4.6/4.4 10.5/7.5 total Δhr (bpm) 1.6 3.8 10.7 drug effect* - 2.2 9.1 * 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 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.

alembic pharmaceuticals limited at 1-866-210-9797. manufactured by: alembic pharmaceuticals limited (formulation division), panelav 389350, gujarat, india manufactured for: alembic pharmaceuticals, inc. bedminster, nj 07921, usa revised: 08/2021