Bisoprolol

Concurrent use of rifampin increases the metabolic clearance of Zebeta, resulting in a shortened elimination half-life of Zebeta. 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 Zebeta on prothrombin time in patients on stable doses of warfarin.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use /with Zebeta/ can increase the risk of bradycardia.

Zebeta 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.

Zebeta 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 Zebeta may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Zebeta be discontinued for several days before the withdrawal of clonidine.

beta-Blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.

Bisoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to bisoprolol. Thus, hepatotoxicity due to bisoprolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery upon withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a structure estimation method(2), indicates that bisoprolol is expected to have high mobility in soil(SRC). The estimated pKa1 of bisoprolol is 9.27(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Bisoprolol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A 37.9% of its Theoretical Oxygen Demand in 75 days using an activated sludge and the Manometric respirometry test(5) suggests that biodegradation may be a slow environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a structure estimation method(2), indicates that bisoprolol is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa1 of 9.27(3) indicates bisoprolol will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), a BCF of 0.2(5), indicates that bioconcentration in aquatic organisms is low. Half-lives of 27.7 and 8.6 days were measured for bisopropol using two natural sediments and respective river waters(6), indicating that biodegradation may be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bisoprolol, which has an estimated vapor pressure of 2.9X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase bisoprolol may be removed from the air by wet and dry deposition(SRC). Bisoprolol exhibited half-lives of 15-70 hours when exposed to a high pressure vapor mercury lamp (250-600 nm)(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

A common adverse effect of cardiovascular blockers is bradycardia, decreasing heart rate and strength of contraction due to its negative chronotropic and inotropic effects. Bisoprolol also decreases cardiac output; therefore, it decreases exercise capacity. Blocking beta receptors on the SA and AV node always carries a risk of heart block. It correlates less frequently with exacerbating peripheral diseases such as the Raynaud phenomenon, bronchoconstriction, and hypoglycemia than non-selective beta-blockers.

IDENTIFICATION AND USE: Bisoprolol is a beta-Adrenergic blocking agent, sometimes under the drug name Zebeta, which is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents. HUMAN EXPOSURE AND TOXICITY: The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. There have been at least two reported cases where a switch from propranolol to bisoprolol resulted in worsening of arrhythmia control. An elderly person died of uncontrolled bradycardia in a hospital after being mistakenly given a higher-than-prescribed dose of bisoprolol fumarate. However, it was determined that the patient had a mutation within cytochrome P2D6, which influences metabolism of the drug. ANIMAL STUDIES: Fetotoxicity in rats occurred at 125 times the maximum recommended human dose (MRHD) of bisoprolol fumarate on a body-weight-basis, and maternal toxicity occurred at 375 times the MRHD. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day (31 times the MRHD based on body-weight), but increased early resorptions. 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 cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays. Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice and rats. No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 123 mg/kg/day.

The toxicity of cardio-selective beta-blockers occurs after ingesting a high dose of the drug, either intentionally or unintentionally. Toxicity can be asymptomatic in some patients, but treatment is always required. Patients in such cases usually present with bradycardia and hypotension. In addition, selective beta-blockers in high doses lose their selectivity, causing patients to demonstrate signs of respiratory distress, congestive heart failure, and neurological manifestations, such as confusion and mental retardation, hypoglycemia, and hyperkalemia.

Bisopropanol concentrations ranged from 0.12 to 0.16 ug/L in effluent from a sewage treatment plant in Frankfurt, Germany. Influent concentrations ranged from 0.35 to 0.49 ug/L(1). The compound was detected in 97% of samples from 90 EU wastewater treatment plant effluents, at an average concentration of 41.6 ng/L and a maximum concentration of 423 ng/L. Sampling was conducted in 2010; detection limit = 0.1 ng/L(2).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of bisoprolol can be estimated to be 140(SRC). According to a classification scheme(2), this estimated Koc value suggests that bisoprolol is expected to have high mobility in soil. Log Koc values of 1.87-2.15 and 2.12 have been reported in sediments from the Burgen (0.74 total organic carbon, clay/silt 10%) and Dausenau (4.36% total organic carbon, 47% clay/silt) rivers, respectively, Germany(3), corresponding to Koc values of 74-141 and 131, respectively(SRC). However, adsorption is affected by the acidity of the soil/substrate(SRC). The estimated pKa1 of bisoprolol is 9.27(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/CASE REPORTS/ 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.

/CASE REPORTS/ An elderly person died of uncontrolled bradycardia in a hospital. The doctor had prescribed 1.35 mg of bisoprolol fumarate orally, but a nurse mistakenly gave the patient 10 mg of the drug 9 hours prior to her death. Bisoprolol was detected in her blood by liquid chromatography-mass spectrometry at a concentration of 176 ng/mL. Even if the patient had chronic heart failure, this concentration is double the expected value. This patient was found to have a mutation within cytochrome P2D6, with thymidine substituted for cytosine at position 100 and cytosine for guanine at position 4180, causing proline to serine and threonine to serine amino acid substitutions. This mutation in the intermediate metabolizer allele reportedly reduces enzyme activity by half. However, in addition to the type of cytochrome P450 allelic variant, the amount of enzyme product influences metabolism of this drug. In this case, the high blood concentration of bisoprolol was only partly attributable to an error in prescription; its concentration was inexplicably high.

/CASE REPORTS/ Propranolol in slow-release form has been the first-line treatment in long QT (LQT) until it was withdrawn from the market. We describe two cases where a switch to bisoprolol resulted in worsening of arrhythmia control: A man with LQT2, asymptomatic on propranolol, experienced syncope after switching to bisoprolol 5 mg daily. He switched back to propranolol and has remained asymptomatic during subsequent 12 months. A man with classical Jervell Lange-Nielsen syndrome, previous gangliectomy, and ICD implantation, switched to bisoprolol 5 mg daily. Four months later he experienced a tachycardia storm. He switched back to propranolol and has remained free from arrhythmias during subsequent 12 months.

Bisopropol not detected in bream (Abramis brama) and roach (Rutilus rutilus) from Lake Haapajarvi, Finland, caught on May 24, 2010. The lake receives effluent from a wastewater treatment plant via the Rakkolanjoki river. It was not detected in the same species that were sampled on July 1, 2011 from Lake Saimma in southern Finalnd, which is not influenced by municipal waste water(1).

AEROBIC: Half-lives of 27.7 and 8.6 days were measured for bisopropol (5 ug dissolved in methanol) using two natural sediments and respective river water of low anthropogenic impact from the Baybreach and Unterbach streams, respectively, near Dausenau, Germany(1). Bisoprolol, present at 50 mg/L, reached 37.9% (75.4% with added carbon source of NaAc) of its Theoretical Oxygen Demand in 75 days using an activated sludge from a sewage treatment plant in Jyvaskyla, Finland and the Manometric respirometry test (OECD test 301F). Based on these results, bisoprolol is considered moderately biodegradable under aerobic conditions(2).

ANAEROBIC: Bisoprolol, present at 1000 mg/L (methane evolution) showed a methane production of 15.7 mL in 161 days using a digester sludge inoculum at 31.5 g/L from a sewage treatment plant in Jyvaskyla, Finland. An averaged of 28% removal was observed using an initial bisoprolol concentration of 100 ug/L. Based on these results, bisoprolol is considered moderately persistent under anaerobic conditions(1).

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

bisoprolol

Zebeta®

Beta blockers

3

less-DILI-concern drugs

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including bisoprolol fumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Bisoprolol fumarate/

MEDICATION

Adrenergic beta-1 Receptor Antagonists; Antihypertensive Agents; Sympatholytics

Use (kg; approx.) in Germany (2009): >7500

Table: Bisoprolol Fumarate Preparations [Table#8328]

Table: Bisoprolol Fumarate Combination Preparations [Table#8329]