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 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 over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol 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.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1-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 beta1-selectivity is not absolute, the lowest possible dose of bisoprolol fumarate should be used with therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be made available.
Anesthesia and Major Surgery
If bisoprolol treatment is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. See Overdosage for information on treatment of bradycardia and hypotension.
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. 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.
Impaired Renal or Hepatic Function
Use caution in adjusting the dose of bisoprolol in patients with renal or hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Bisoprolol 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 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 be discontinued for several days before the withdrawal of clonidine.
Bisoprolol 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, resulting in a shortened elimination half-life of bisoprolol. 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 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.
Information for Patients
Patients, especially those with coronary artery disease, should be warned about discontinuing use of bisoprolol 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body-weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body-surface-area-basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.
Reproduction studies in rats did not show any impairment of 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.
Pregnancy Category C
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 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 31 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 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 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. 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 dropout for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.