Pr
phl-BISOPROLOL
(Bisoprolol Fumarate Tablets, USP) 5 mg and 10 mg
b
-adrenoceptor blocking agent
6111 Royalmount Ave., Suite 100 March 27, 2008 Montreal, Quebec H4P 2T4
SUMMARY PRODUCT INFORMATION. 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 13 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 16 DOSAGE FORMS, COMPOSITION AND PACKAGING 16
PHARMACEUTICAL INFORMATION 17 CLINICAL TRIALS 17 DETAILED PHARMACOLOGY 18 TOXICOLOGY 18 REFERENCES 27
PART III: CONSUMER INFORMATION
Pr
phl-BISOPROLOL
(Bisoprolol Fumarate Tablets, USP) 5 mg and 10 mg
b
-adrenoceptor blocking agent
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablets: 5 mg and 10 mg | None. For a complete listing see Dosage Forms, Composition and Packaging section. |
Adults
phl-BISOPROLOL (Bisoprolol Fumarate) is indicated for:
the management of patients with mild to moderate hypertension
It may be used alone or in combination with other antihypertensive agents, particularly thiazide diuretics. Bisoprolol Fumarate is not recommended for the emergency treatment of hypertensive crisis.
phl-BISOPROLOL (bisoprolol fumarate) is contraindicated in patients with cardiogenic shock, overt heart failure, second or third degree A-V block, right ventricular failure secondary to pulmonary hypertension, and sinus bradycardia.
Appropriate laboratory tests for monitoring renal, hepatic, and hematopoietic function should be performed at regular intervals during long-term treatment with Bisoprolol Fumarate.
Information for the patient
Patients, especially those with coronary artery disease, should be warned against discontinuing use of Bisoprolol Fumarate 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 the n-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be used with caution.
Anaesthesia:
It is not advisable to withdraw beta-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using Bisoprolol Fumarate with anaesthetic 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 beta-adrenoceptor blocking agents have been subject to protracted severe hypotension during anaesthesia. Difficulty in restarting the heart and maintaining the heart beat has also been reported (see also OVERDOSAGE). In emergency surgery, since Bisoprolol Fumarate is a competitive antagonist at beta- adrenoceptor sites, its effects may be reversed, if required, by sufficient doses of such agonists as isoproterenol or noradrenaline.
Abrupt Cessation of Therapy with Bisoprolol Fumarate:
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 Fumarate over approximately two weeks and the patient should be carefully observed. The same frequency of administration should be maintained. If withdrawal symptoms occur, therapy with Bisoprolol Fumarate should be reinstituted, at least temporarily.
Diabetes Mellitus and Hypoglycemia:
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Non-selective ss-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Therefore, Bisoprolol Fumarate 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.
Cardiac Failure
Special caution should be exercised when administering Bisoprolol Fumarate to patients with a history of severe heart failure. Safety and effectiveness of bisoprolol doses higher than 10 mg per 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 Fumarate 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 Fumarate when the two drugs are used concomitantly. The effects of b-blockers and digitalis are additive in depressing A-V 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 Fumarate therapy should be immediately withdrawn.
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.
Sinus Bradycardia:
Severe sinus bradycardia, resulting from unopposed vagal activity following 3-blockade, may occur with the use of Bisoprolol Fumarate. In such cases, the dosage should be reduced or Bisoprolol Fumarate discontinued.
Thyrotoxicosis:
In patients with thyrotoxicosis, possible deleterious effects from long-term use of Bisoprolol Fumarate 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 Fumarate is to be discontinued, withdrawal should be gradual and the patients monitored closely.
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 alpha 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 beta 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.
Oculomucocutaneous Syndrome:
Various skin rashes have been reported with b-blockers, including Bisoprolol Fumarate. 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 Fumarate 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.
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 AND ADMINISTRATION Section).
Bronchospastic Disease:
In general, patients with bronchospastic pulmonary disease should not receive b-blockers. However, because Bisoprolol Fumarate (bisoprolol fumarate) is relatively b1-selective, it may be used cautiously in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since b1-selectivity is not absolute, the lowest possible dose should be employed, a b2-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.
Bisoprolol fumarate was not teratogenic in rats at doses up to 150 mg/kg/day, which is 375 times the maximum recommended human daily dose. 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. Bisoprolol fumarate 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 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. If use of
Bisoprolol Fumarate is considered essential, then mothers should stop nursing.
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Bisoprolol Fumarate 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 Fumarate. Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose.
Safety and effectiveness in children have not been established.
There are no specific laboratory tests recommended for the management of patients receiving Bisoprolol Fumarate.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
In two multi-centre, 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 one 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. The following table (Table 1) presents the adverse experiences, whether or not drug related, reported by >1% of all patients (n=404) enrolled in the two placebo-controlled trials of Bisoprolol Fumarate) given in single daily doses of 2.5 - 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 below in Table 1
TABLE 1
Adverse Experience (>1%): Placebo-Controlled Trials (n=404)
Body System/Adverse Experience All Adverse Experiences n (%)
Musculo-skeletal
arthralgia 11 (2.7) | |
|---|---|
| myalgia | 7 (1.7) |
| muscle cramps | 6 (1.5) |
| Central Nervous System | |
| dizziness | 14 (3.5) |
| headache | 44 (10.9) |
| paraesthesia | 5 (1.2) |
| hypoaesthesia | 6 (1.5) |
| Autonomic Nervous System | |
| dry mouth | 5 (1.2) |
| Hearing and Vestibular | |
| earache | 5 (1.2) |
| Psychiatric impotence | 5 (1.2) |
| insomnia | 10 (2.5) |
| somnolence | 5 (1.2) |
| Gastrointestinal | |
| diarrhea | 14 (3.4) |
| dyspepsia | 5 (1.2) |
| nausea | 9 (2.2) |
| vomiting | 6 (1.5) |
| Respiratory coughing | 10 (2.5) |
| dyspnea | 6 (1.5) |
| pharyngitis | 9 (2.2) |
| rhinitis | 16 (4.0) |
| sinusitis | 9 (2.2) |
| URT infection | 20 (5.0) |
| Body as Whole | |
| asthenia | 6 (1.5) |
| chest pain | 6 (1.5) |
| fatigue | 33 (8.2) |
| edema peripheral | 12 (3.0) |
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 %), 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 one adverse experience. Out of the total number of patients enrolled, 12 (8.3%) discontinued therapy due to an adverse experience or an intercurrent illness.
Other Clinical Trial Adverse Drug Reactions ( >1%)
The table below (Table 2) presents the adverse experiences reported by at least 1% all of patients (n=144) enrolled in the long-term, open-label, extension study in which patients received doses of Bisoprolol Fumarate ranging from 5 - 20 mg daily.
TABLE 2
Adverse Experiences (>1%) : Long-Term, Open-Label, Extension Study (n=144)
Body SystemlAdverse Experience All Adverse Experiences n (%)
Musculo-skeletal
arthralgia 6 (4.2)
myalgia 3 (2.1)
muscle cramps 3 (2.1)
Central Nervous System
dizziness 7 (4.9)
headache 12 (8.3)
neuralgia 2 (1.4)
Vision
eye abnormality 2 (1.4)
vision abnormal 2 (1.4)
Hearing and Vestibular
earache 3 (2.1)
tinnitus 2 (1.4) | |
|---|---|
| depression | 2 (1.4) |
| impotence | 3 (2.1) |
| libido decreased | 3 (2.1) |
| insomnia | 2 (1.4) |
| paroniria | 2 (1.4) |
Psychiatric
| abdominal pain | 3 (2.1) |
| diarrhea | 4 (2.8) |
| dyspepsia | 2 (1.4) |
Gastrointestinal
Respiratory
| bronchitis | 4 (2.8) |
| bronchospasm | 2 (1.4) |
| coughing | 6 (4.2) |
| pharyngitis | 6 (4.2) |
| rhinitis | 12 (8.3) |
| sinusitis | 7 (4.9) |
| URT Infection | 10 (6.9) |
TABLE 2 (Continued)
Adverse Experiences (>1%): Long-Term, Open-Label, Extension Study (n=144)
Body System/Adverse Experience All Adverse
Body as Whole
n (%)
allergy 2 (1.4)
back pain 3 (2.1)
Chest pain 3 (2.1)
fatigue 10 (6.9)
fever 3 (2.1)
hot flushes 2 (1.4)
malaise 2 (1.4)
edema generalized 2 (1.4)
edema peripheral 5 (3.5)
pain 3 (2.1)
traumatic injury 3 (2.1)
Less Common Clinical Trial Adverse Drug Reactions (<1%)
The following is a list of spontaneous adverse experiences reported with Bisoprolol Fumarate since its entry into the U.S. 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:
Central Nervous System:
Dizziness, vertigo, headache, paraesthesia, somnolence, decreased concentration/memory, aphasia, insomnia, muscle contractions (involuntary), paresis, sleep disturbances, sleepiness, syncope, tingling sensation, coma, encephalopathy, speech disorder, hallucination, confusion.
Autonomous 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, arrhythmia.
Skin:
Rash, pruritus, alopecia, angioedema, exfoliative dermatitis, hyperpigmentation, psoriaform rash, skin photosensitivity, epidermal necrolysis, erythema multiforma, sclerodeiiua, skin discolouration, urticaria.
Special Senses:
Ocular pain/pressure, abnormal lacrimation, taste abnormalities, ageusia, anosmia, conjunctivitis, visual disturbances.
Metabolic:
Hypoglycaemia
Respiratory:
Asthma/bronchospasm, dyspnea, shortness of breath, pulmonary edema, pneumonitis, respiratory insufficiency.
Hematologic:
Purpura, vasculitis, peripheral ischemia.
Gastrointestinal:
Vomiting, diarrhea.
Musculoskeletal:
Muscle cramps, twitching/tremor, arthralgia, myalgia.
Genito-Urinary:
Peyronie's disease, galactorrhea, mastalgia, still-birth.
General:
Fatigue, asthenia, malaise, edema, weight gain, death, scleroderma, overdose effect, asthenia.
Abnormal Hematologic and Clinical Chemistry Findings
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 two U.S., well-controlled studies versus placebo with Bisoprolol Fumarate treatment for 4 - 12 weeks, the incidence of concomitant elevations in SGOT and SGPT of between 1 - 2 times normal was 3.9% for Bisoprolol Fumarate compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal. Experience from long-term, uncontrolled studies with Bisoprolol Fumarate treatment for 6 - 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT of between 1 - 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 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 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 titre, although about one-third of these patients subsequently reconverted to a negative titre while on continued therapy.
Other b-blocking Agents: Bisoprolol Fumarate 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 Fumarate 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 co- administered, 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 Fumarate 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 antiarrhythrnic 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 Fumarate, resulting in a shortened elimination half-life of Bisoprolol Fumarate. Therefore, compounds with enzymatic induction potential should be administered with caution to patients receiving Bisoprolol Fumarate 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 Fumarate on prothrombin time in patients on stable doses of warfarin.
Exaggerated hypertensive responses have been reported from the combined use of beta adrenergic antagonists and alpha adrenergic stimulants including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving b-blockers should be warned of this potential hazard.
Interactions with food have not been established.
Interactions with herbal products have not been established.
There are no known interactions between Bisoprolol Fumarate and laboratory tests.
Dosing Considerations:
Patients with Renal or Hepatic Impairment
Elderly
Children
In the treatment of mild to moderate hypertension, phl-BISOPROLOL (Bisoprolol Fumarate) 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.
Recommended Dose and Dosage Adjustment
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 phl-BISOPROLOL is not dialysable, drug replacement is not necessary in patients undergoing dialysis.
Elderly:
In the elderly, it is not usually necessary to adjust the dose, unless there is also significant renal or hepatic dysfunction (see WARNINGS AND PRECAUTIONS).
Children:
There is no pediatric experience with phl-BISOPROLOL, therefore its use cannot be recommended for children.
Patients should consult the doctor or the pharmacist on what to do in case of a missed dose.
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 Fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered. In general, if overdose occurs, therapy with Bisoprolol Fumarate should be stopped and supportive, symptomatic treatment should be provided. Patients should be monitored closely. Limited data suggest that Bisoprolol Fumarate 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 IV 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. Intravenous glucagon has been described to be useful.
Hypotension:
IV fluids and vasopressors such as dopamine or norepinephrine should be administered. Monitor blood pressure continuously. Intravenous 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 (b2 stimulants) and/or IV aminophylline.
Hypoglycemia:
Administer IV 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 Fumarate 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 Fumarate. However, complications of excess isoproterenol should not be overlooked.
Mechanism of Action
Bisoprolol Fumarate is a synthetic b1-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 b2-adrenoceptors, located chiefly in the bronchial and vascular musculature.
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. 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
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 isoproterenolinducted tachycardia. The maximal effect occurred with 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.
Pharmacokinetics
Absorption:
Bisoprolol fumarate 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 famarate is less than 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 - 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 Fumarate results in less than two fold 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 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 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 cytochrorne P450 II D6 (debrisoquin hydroxylase). In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately three-fold compared to healthy subjects.
Special Populations and Conditions
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.
Bisoprolol Fumarate tablets should be stored at controlled room temperature (15 to 30degC/ 59 to 86degF). No other special storage conditions are necessary.
phl-BISOPROLOL (Bisoprolol Fumarate) 5 mg tablets contain the following non-medicinal ingredients: Colloidal silicon dioxide, Copovidone, Dibasic calcium phosphate anhydrous, Ferric oxide red, Hydroxypropyl methyl cellulose, Isopropyl alcohol, Magnesium stearate, Microcrystalline cellulose, Pregelatinised starch, Titanium dioxide and Triacetin. phl-BISOPROLOL 10 mg tablets contain the following non-medicinal ingredients: Colloidal silicon dioxide, Copovidone, Dibasic calcium phosphate anhydrous, HPMC 2910/Hypromellose 5 cP, Isopropyl alcohol, Magnesium stearate, Microcrystalline cellulose, Pregelatinised starch, Titanium dioxide and Triacetin/Glycerol triacetate. phl-BISOPROLOL are available in HDPE bottles of 100 format for both strengths.
Salmon pink, round, biconvex, coated tablet debossed with "P" logo on one side and scored on the other side with an interlocking "55".
White, round, biconvex, coated tablet debossed with "P" logo on one side and "10" on the other side.