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| Medication |
Strength |
Quantity |
| Monocor (Bisoprolol) |
10mg |
100 |
| Monocor (Bisoprolol) |
5mg |
100 |
| Monocor (bisoprolol - generic) |
10 mg |
100 |
| Monocor (bisprolol - generic) |
5 mg |
100 |
Monocor
Bisoprolol Fumarate
Monocor - Monocor Side Effects - Monocor Information
Pharmacology: Bisoprolol is a synthetic b 1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. This preferential effect is not absolute, however, and at higher doses bisoprolol may also inhibit b 2-adrenoceptors, located chiefly in the bronchial and vascular musculature.
Pharmacodynamics: The most prominent effect of bisoprolol 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.
The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include: antagonism of b-adrenoceptors to decreased cardiac output; inhibition of renin release by the kidneys; and diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
In normal volunteers, bisoprolol therapy resulted in a reduction of exercise and isoproterenol-inducted tachycardia. The maximal effect occurred within 1 to 4 hours postdosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that bisoprolol significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods and, with rapid atrial stimulation, prolongs AV nodal conduction.
Bisoprolol is well absorbed following oral administration. The absolute bioavailability after a 10 mg dose is greater than 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol is less than 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with bisoprolol results in 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 with 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 administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the 2 enantiomers are similar.
Bisoprolol 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 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 liver cirrhosis, the rate of elimination of bisoprolol fumarate is more variable and significantly slower than that in healthy subjects, with plasma half-life ranges from 8.3 to 21.7 hours.
Indications: Management of patients with mild to moderate hypertension. It may be used alone or in combination with other antihypertensive agents, particularly thiazide diuretics.
Bisoprolol is not recommended for the emergency treatment of hypertensive crisis.
Contraindications: In patients with cardiogenic shock, overt heart failure, second or third degree AV block, right ventricular failure secondary to pulmonary hypertension, and sinus bradycardia.
Warnings: Cardiac Failure: Special caution should be exercised when administering bisoprolol to patients with a history of severe heart failure. Safety and effectiveness of bisoprolol doses higher than 10 mg/day in patients with heart failure have not been established. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. In general, b-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. Bisoprolol acts selectively without abolishing the effects of digitalis. However, the positive inotropic effect of digitalis may be reduced by the negative inotropic effect of bisoprolol when the 2 drugs are used concomitantly. The effects of b-blockers and digitalis are additive in depressing AV conduction.
Patients Without a History of Cardiac Failure: In patients without a history of cardiac failure continued depression of the myocardium with b-blockers in some cases lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately and the response observed closely. If cardiac failure continues, bisoprolol therapy should be immediately withdrawn.
Abrupt Cessation of Therapy With Bisoprolol: 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 b-blockers. 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 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. If withdrawal symptoms occur, therapy with bisoprolol 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.
Oculomucocutaneous Syndrome: Various skin rashes have been reported with b-blockers, including bisoprolol. A severe syndrome (oculomucocutaneous syndrome), whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis, has occurred with the chronic use of one b-adrenoceptor blocking agent (practolol). This syndrome has not been observed with bisoprolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Sinus Bradycardia: Severe sinus bradycardia, resulting from unopposed vagal activity following b-blockade, may occur with the use of bisoprolol. In such cases, the dosage should be reduced or bisoprolol discontinued.
Thyrotoxicosis: In patients with thyrotoxicosis, possible deleterious effects from long-term use of bisoprolol have not been adequately appraised.
b-adrenoceptor blockade may mask clinical signs of hyperthyroidism, such as tachycardia or its complications, and gives a false impression of improvement. Abrupt withdrawal of b-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or precipitate thyroid storm.
Therefore, in such patients from whom bisoprolol is to be discontinued, withdrawal should be gradual and the patients monitored closely.
Precautions: Appropriate laboratory tests for monitoring renal, hepatic, and hematopoietic function should be performed at regular intervals during long-term treatment with bisoprolol.
Bronchospastic Disease: In general, patients with bronchospastic pulmonary disease should not receive b-blockers. However, because bisoprolol is relatively b 1-selective, it may be used cautiously in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since b 1-selectivity is not absolute, the lowest possible dose should be employed, a b 2-agonist (bronchodilator) should be made available, and the patient should be monitored closely. In patients already on bronchodilator therapy the dose may have to be increased.
Anesthesia: It is not advisable to withdraw b-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using bisoprolol with anesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg i.v.).
Some patients receiving b-adrenoceptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting the heart and maintaining the heart beat has also been reported (see also Overdose: Symptoms and Treatment).
In emergency surgery, since bisoprolol is a competitive antagonist at beta-adrenoceptor sites, its effects may be reversed, if required, by sufficient doses of such agonists as isoproterenol or norepinephrine.
Allergic Type Reaction: There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the beta-blockers and the problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm while, on the other, these doses can be associated with excessive a-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of b-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm or norepinephrine to overcome hypotension.
Risk of Anaphylactic Reaction: While taking b-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.
Diabetes Mellitus and Hypoglycemia: Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective b-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Therefore, bisoprolol should be used with caution in patients subject to spontaneous hypoglycemia, or in diabetic patients (especially those with labile diabetes) receiving insulin or oral hypoglycemic agents.
Impaired Renal or Hepatic Function: Appropriate laboratory tests for monitoring renal, hepatic and hematopoietic function should be performed at regular intervals during long-term treatment. Use caution in adjusting dose in hepatic and renal impaired patients (see Dosage).
Geriatrics: Bisoprolol has been used in elderly patients with essential hypertension. Although the response rates and mean decreases in diastolic blood pressure were similar to that in younger patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol. Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose.
Pregnancy : Bisoprolol was not teratogenic in rats at doses up to 150 mg/kg/day, which is 375 times the maximum recommended human daily dose. Bisoprolol was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. Bisoprolol was not teratogenic in rabbits at doses up to 12.5 mg/kg/day, which is 31 times the maximum recommended human daily dose, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.
There are no studies in pregnant women. Bisoprolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation : Small amounts of bisoprolol (<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. If use of bisoprolol is considered essential, then mothers should stop nursing.
Children: Safety and effectiveness in children have not been established.
Drug Interactions : Other b-blocking Agents: Bisoprolol should not be combined with other b-blocking agents.
Catecholamine-depleting Drugs: Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be monitored closely because the added b-adrenergic blocking action of bisoprolol may produce excessive reduction of sympathetic activity.
Centrally Active Antihypertensive Agents: b-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the 2 drugs are coadministered, the b-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by b-blocker therapy, the introduction of b-blockers should be delayed for several days after clonidine administration has stopped (see also prescribing information for clonidine).
Antiarrhythmic Agents: 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.
Calcium Channel Blockers: Combined use of b-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of SA and AV conduction, particularly in patients with impaired ventricular function or conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure.
Pharmacokinetic Interactions : Concurrent use of rifampin increases the metabolic clearance of bisoprolol, resulting in a shortened elimination half-life of bisoprolol. Therefore, compounds with enzymatic induction potential should be administered with caution to patients receiving bisoprolol therapy. Pharmacokinetic studies document no clinically relevant adverse interactions with other agents given concomitantly, including thiazide diuretics, digoxin, and cimetidine. There was no effect of bisoprolol on prothrombin time in patients on stable doses of warfarin.
Exaggerated hypertensive responses have been reported from the combined use of b-adrenergic antagonists and a-adrenergic stimulants including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving b-blockers should be warned of this potential hazard.
Information to Be Provided to the Patient: Patients, especially those with coronary artery disease, should be warned against discontinuing use of bisoprolol without a physicians'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 the b-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol should be used with caution.
Adverse Effects: In 2 multicentre, placebo-controlled clinical trials involving 404 mild-to-moderate hypertensive patients, the most frequently reported adverse reactions (>2%), whether or not drug related, were: arthralgia (2.7%), dizziness (3.5%), headache (10.9%), insomnia (2.5%), diarrhea (3.5%), nausea (2.2%), coughing (2.5%), pharyngitis (2.2%), rhinitis (4.0%), sinusitis (2.2%), URT infection (5.0%), fatigue (8.2%), and peripheral edema (3%).
In total, 187 out of 404 patients (46.3%) reported at least 1 adverse event. Overall the events reported were mild to moderate in severity. Twenty-seven out of 404 patients (6.7%) discontinued therapy due to an adverse event or an intercurrent illness.
Table I presents the adverse experiences, whether or not drug related, reported by >1% of all patients (n=404) enrolled in the 2 placebo-controlled trials of bisoprolol given in single daily doses of 2.5 to 40 mg. The adverse drug reactions that appear to be dose related are bradycardia, diarrhea, asthenia, fatigue and sinusitis. As the incidence of bradycardia is 0.5%, it is the only dose related adverse experience not listed in Table I.
In one long-term, open-label, extension study involving 144 hypertensive patients, the most frequently reported adverse experiences (>2%), whether or not drug related were: arthralgia (4.2%), myalgia (2.1%), muscle cramps (2.1%), dizziness (4.9%), headache (8.3%), earache (2.1%), impotence (2.1%), libido decrease (2.1%), abdominal pain (2.1%), diarrhea (2.8%), bronchitis (2.8%), coughing (4.2%), pharyngitis (4.2%), rhinitis (8.3%), sinusitis (4.9%), URT infection (6.9%), back pain (2.1%), chest pain (2.1%), fatigue (6.9%), fever (2.1%), peripheral edema (3.5%), pain (2.1%) and traumatic injury (2.1%).
The adverse experiences reported were generally mild to moderate in severity. Seventy-nine out of 144 patients (54.9%) reported at least 1 adverse experience. Out of the total number of patients enrolled, 12 (8.3%) discontinued therapy due to an adverse experience or an intercurrent illness.
Table II presents the adverse experiences reported by at least 1% of all patients (n=144) enrolled in the long-term, open-label, extension study in which patients received doses of bisoprolol ranging from 5 to 20 mg daily.
The following is a list of spontaneous adverse experiences reported with bisoprolol since its entry into the US market and the markets of some European countries. In these cases, an incidence or causal relationship cannot be accurately determined. The adverse experiences are listed according to body system and are as follows:
CNS: dizziness, vertigo, headache, paresthesia, somnolence, decreased concentration/memory, aphasia, insomnia, muscle contractions (involuntary), paresis, sleep disturbances, sleepiness, syncope, tingling sensation, coma, encephalopathy, speech disorder, hallucination and confusion.
Autonomic Nervous System: dry mouth.
Cardiovascular: bradycardia, palpitations and other rhythm disturbances, hypotension, dyspnea on exertion, embolism, extrasystoles, atrial fibrillation, left cardiac failure, myocardial infarction, Raynaud-like disorder, hypertension, cardiac failure, circulatory failure, AV block, cardiac arrest, tachycardia, ventricular fibrillation and arrhythmia.
Skin: rash, pruritus, alopecia, angioedema, exfoliative dermatitis, hyperpigmentation, psoriaform rash, skin photosensitivity, epidermal necrolysis, erythema multiforma, scleroderma, skin discoloration and urticaria.
Special Senses: ocular pain/pressure, abnormal lacrimation, taste abnormalities, ageusia, anosmia, conjunctivitis and visual disturbances.
Metabolic: hypoglycemia.
Respiratory: asthma/bronchospasm, dyspnea, shortness of breath, pulmonary edema, pneumonitis and respiratory insufficiency.
Hematologic: purpura, vasculitis and peripheral ischemia.
Gastrointestinal: vomiting and diarrhea.
Musculoskeletal: muscle cramps, twitching/tremor, arthralgia and myalgia.
Genitourinary: Peyronie's disease, galactorrhea, mastalgia and stillbirth.
General: fatigue, asthenia, malaise, edema, weight gain, death, scleroderma, overdose effect and asthenia.
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 abnormalities have been reported. In 2 US, well-controlled studies vs placebo with bisoprolol treatment for 4 to 12 weeks, the incidence of concomitant elevations in AST and ALT of between 1 to 2 times normal was 3.9% for bisoprolol compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.
Experience from long-term, uncontrolled studies with bisoprolol treatment for 6 to 18 months, the incidence of one or more concomitant elevations in AST and ALT of between 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in AST and ALT 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.
Other laboratory changes include small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreased in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol.
As with other b-blockers, ANA conversions have also been reported on bisoprolol. About 15% of patients in long-term studies converted to a positive titre, although about one-third of these patients subsequently reconverted to a negative titre while on continued therapy.
Overdose: Symptoms: The most common signs expected with overdosage of a b-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted.
Treatment: Sympathomimetic agents were given in some cases, and all patients recovered. In general, if overdose occurs, therapy with bisoprolol should be stopped and supportive, symptomatic treatment should be provided. Patients should be monitored closely. Limited data suggest that bisoprolol is not dialysable.
Based on the expected pharmacologic actions and recommendations for other b-blockers, the following general measures should be considered when clinically warranted:
Bradycardia: Administer i.v. 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. I.V. glucagon has been described to be useful.
Hypotension: I.V. fluids and vasopressors such as dopamine or norepinephrine should be administered. Monitor blood pressure continuously. I.V. 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). Glucagon has been reported to be useful.
Bronchospasm: Administer bronchodilator therapy such as isoproterenol or terbutaline (b 2-stimulants) and/or i.v. aminophylline.
Hypoglycemia: Administer i.v. glucose.
Based on the severity of symptoms, management may require intensive support care and facilities for administering cardiac and respiratory support.
It should be remembered that bisoprolol is a competitive antagonist of isoproterenol and hence large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of bisoprolol. However, complications of excess isoproterenol should not be overlooked.
Dosage: In the treatment of mild to moderate hypertension bisoprolol must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily either added to a diuretic or alone. If the response to 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily. An appropriate interval for dose titration is 2 weeks.
Increasing the dose beyond 20 mg once daily produces only a small incremental benefit.
Patients with Renal or Hepatic Impairment: In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine, clearance less than 40 mL/min), as in other patients, the initial daily dose should be 5 mg. Because of the possibility of accumulation, caution must be used in dose-titration. Since limited data suggest that bisoprolol is not dialysable, drug replacement is not necessary in patients undergoing dialysis.
Geriatrics: In the elderly, it is not usually necessary to adjust the dose, unless there is also significant renal or hepatic dysfunction (see Precautions, Geriatrics).
Children: There is no pediatric experience with bisoprolol, therefore its use cannot be recommended for children.
Supplied: 5 mg: Each salmon pink, round, biconvex, film-coated tablet, approximately 7 mm in diameter, embossed 5 on one side and scored on the other with an interlocking LL, contains: bisoprolol fumarate 5 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, red iron oxide, silicon dioxide, titanium dioxide and yellow iron oxide. White plastic bottles of 100.
10 mg: Each white, round, biconvex, film-coated tablet, approximately 7 mm in diameter, embossed 10 on one side and interlocking LL on the other, contains: bisoprolol fumarate 10 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, silicon dioxide and titanium dioxide. White plastic bottles of 100.
Store at controlled room temperature (15 to 30°C). No other special storage conditions are necessary.
IMPORTANT NOTE: THE FOLLOWING INFORMATION IS INTENDED TO SUPPLEMENT, NOT SUBSTITUTE FOR, THE EXPERTISE AND JUDGMENT OF YOUR PHYSICIAN, PHARMACIST OR OTHER HEALTHCARE PROFESSIONAL. IT SHOULD NOT BE CONSTRUED TO INDICATE THAT USE OF THE DRUG IS SAFE, APPROPRIATE, OR EFFECTIVE FOR YOU. CONSULT YOUR HEALTHCARE PROFESSIONAL BEFORE USING THIS DRUG.
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