Bisomed 5mg

Description

Clinical Pharmacology

Mechanism of Action:
Bisoprolol is a β1 -selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range.

The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:

– Decreased cardiac output.
– Inhibition of renin release by the kidneys.
– Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.

The maximal effect of bisoprolol occurred within 1 to 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, with rapid atrial stimulation and prolongs AV nodal conduction.

Additional information

Pharmacodynamics	The most prominent effect of bisoprolol is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate and decrease in contractility with consequence of decrease cardiac oxygen demand. 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.
Pharmacokinetics	Absorption: Bisoprolol is well absorbed, with absolute bioavailability of approximately 80%. 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. Steady state is attained within 5 days of 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. Absorption is not affected by the presence of food. Distribution: Bisoprolol has low lipophilicity; penetration the through the blood brain barrier is minimal and with low serum protein binding (approximately 30%). The volume of distribution of about 3.5 L/kg. In both young and elderly populations, plasma accumulation is low, and is what would be expected from the first order kinetics and once daily dosing. Metabolism: Bisoprolol is primarily metabolized by the CYP3A4 and CYP2D6(minor). First-pass metabolism of bisoprolol is low (about 20%). Excretion: 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. Less than 2% of the dose is excreted in the feces. 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. In subjects with creatinine clearance less than 40 ml/min, the plasma half-life is increased approximately threefold compared to healthy subjects, and in patients with liver cirrhosis, the elimination of bisoprolol 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.
Indications and Usage for Bisomed Tablet	Treatment of Hypertension: Bisoprolol fumarate tablets are indicated in the management of hypertension as monotherapy or in combination with other classes of antihypertensive agents. According to ACC/AHA guidelines, bisoprolol or other beta blockers are not the first-line treatment for hypertension unless the patient has ischemic heart disease or HFrEF. Treatment of chronic, stable angina pectoris: For long-term management β-Blockers are considered first-line anti-ischemic drugs in most patients with chronic stable angina (According to the 2020 International Society of Hypertension practice guidelines, cardioselective beta-blockers such as bisoprolol should be used, with or without calcium channel blockers, in patients with coronary artery disease). Treatment of stable chronic heart failure (CHF) with reduced systolic left ventricular function: Bisoprolol is used in the treatment plan for compensated heart failure. (According to 2022 AHA/ACC/HFSA guidelines, specific beta-blockers as bisoprolol, are included in guideline directed medical therapy(GDMT) for heart failure with reduced ejection fraction(HFrEF)). Bisoprolol is recommended to reduce mortality and hospitalizations in patients with HFrEF. Myocardial Infarction: The use of bisoprolol correlates with decreased morbidity and mortality post- MI. (Bisoprolol reduces the risk of stroke and coronary artery disease in patients with heart disease). A fixed-dose combination of bisoprolol and hydrochlorothiazide. Atrial Fibrillation. Non approved uses of bisoprolol include: the treatment of migraine, arrhythmia, and tremors and as an anxiolytic.
Dosage and Administration	Hypertension or Chronic, stable angina pectoris: The dose of bisoprolol fumarate should be tailored to the patient’s individualized needs. The usual starting dose is 5 mg once daily. If the 5 mg dose does not produce the desired effect, the dose should be gradually increased to 10 mg. The maximum recommended dose is 20 mg bisoprolol fumarate once daily. Failure With Reduced Ejection Fraction: In addition to the other drugs included in the treatment plan Bisomed must started with the initial dose of 1.25 mg once daily, while the target dose is 10 mg once daily as a maintenance treatment. To optimize GDMT, the dose should be titrated every 1 to 2 weeks by adding 1.25 mg to the last dose based on individual adaptation to the dose symptoms, vital signs, and volume status. Bisoprolol should be started once acute decompensated heart failure is stabilized, and the patient does not require vasopressors or inotropes. Atrial Fibrillation: According to AHA/ACC/HRS guidelines, the dose of bisoprolol for rate control is 2.5 mg to 10 mg PO once daily.
Contraindications	– Hypersensitivity to bisoprolol fumarate, any ingredient in the formulation, or sulfonamides. – Inotropic therapy. – Second or third degree AV block. – Sinoatrial block. – Symptomatic hypotension. – Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome. – Metabolic acidosis. – Acute heart failure or during episodes of heart failure decompensation requiring I.v inotropic therapy. – Cardiogenic shock. – Sick sinus syndrome. – Symptomatic bradycardia. – Severe bronchial asthma. – Untreated phaeochromocytoma.
Warnings and Precautions	Bisoprolol must be used with caution in: – Bronchospasm (bronchial asthma, obstructive airways diseases). – Diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked. – Strict fasting. – Ongoing desensitisation therapy. – First degree AV block. – Prinzmetal’s angina. – Peripheral arterial occlusive disease (intensification of complaints may happen especially during the start of therapy). – General anaesthesia: beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs. – Allergic reactions: As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect. – Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after carefully balancing the benefits against the risks. – In patients with phaeochromocytoma, bisoprolol must not be administered until after alpha-receptor blockade. – Under treatment with bisoprolol the symptoms of a thyrotoxicosis may be asked. – The initiation of treatment with bisoprolol necessitates regular monitoring.
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 fumarate over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol fumarate therapy should be reinstituted, at least temporarily.
Adverse Reactions	Very common (> 1/10): bradycardia. Common (> 1/100, to < 1/10): worsening of heart failure, dizziness, headache, gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation, Feeling of coldness or numbness in the extremities, hypotension, asthenia, fatigue. Uncommon (> 1/1,000, to < 1/100): AV-conduction disturbances, bronchospasm in patients with bronchial asthma or a history of obstructive airways disease, muscular weakness and cramps, sleep disorders, depression, orthostatic hypotension. Rare (> 1/10,000, to < 1/1,000): syncope, reduced tear flow (to be considered if the patient uses lenses), hearing impairment, allergic rhinitis, hepatitis, Potency disorders, hypersensitivity reactions (itching, flush, rash), nightmares, hallucinations, increased triglycerides, increased liver enzymes (ALAT, ASAT). Very rare (< 1/10,000): conjunctivitis, may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Drug Interactions	Combinations not recommended: Bisoprolol fumarate 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 fumarate 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 fumarate be discontinued for several days before the withdrawal of clonidine. -Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block. -Class I antiarrhythmic drugs (e.g. quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased. Combinations to be used with caution: Calcium antagonists such as dihydropyridine derivatives with negative inotropic effect (e.g., nifedipine): Nifedipine decreases myocardial contractility by affecting the amount of calcium. Its concomitant use in patients on beta-blocker treatment may increase the risk of hypotension and reduction of the ventricular pump function with possible development of heart failure in patients with latent cardiac insufficiency. The negative inotropism of nifedipine may precipitate or exacerbate heart failure. Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded. Class-III antiarrhythmic medicinal products (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated. Topical beta-blockers (e.g. eye drops for glaucoma treatment): may add to the systemic effects of bisoprolol. Parasympathomimetic medicines: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia. Insulin and oral antidiabetic medicinal products: Intensification of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia. Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension. Digitalis glycosides: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol. β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents. Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers. Higher doses of adrenaline may be necessary for treatment of allergic reactions. Concomitant use with antihypertensive agents as well as with other medicinal products with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines): may increase the risk of hypotension. Moxisylate: Possibly causes severe postural hypertension. Combinations to be considered: Mefloquine: Increased risk of bradycardia. Monoamineoxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of betablocking agents but also risk of hypertensive crisis. Concurrent use of rifampin: increases the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life of bisoprolol fumarate. However, initial dose modification is generally not necessary.
Use in Specific Population	Pregnancy: Bisoprolol is Category C medicine and should not be used in pregnancy. Breastfeeding: Bisoprolol has low PPB (30%), a long half-life, and a potential risk of accumulation in infants. In addition, there is minimal clinical experience in using it during breastfeeding; consequently, other drugs are preferred, particularly if nursing a newborn or preterm infant. Pediatric Use: No information on pediatric experience with bisoprolol fumarate; there are no approved indications for pediatric patients. Geriatric Use: The dose needs to be adjusted in older patients only if there is significant hepatic or renal dysfunction. Renal Impairment: In Hypertension or Chronic, stable angina pectoris patients with: CrCl >40 & >20 ml/minute/1.73 m: Mild to moderate, no dosage adjustment necessary, starting dose should be 2.5 mg per day, and titrate upwards slowly. CrCl <20 ml/minute/1.73 m: Start with low initial doses (eg, 1.25 to 2.5 mg daily, and consider a reduced maximum dose of 10 mg daily. This dosage may eventually be divided into halves. Hemodialysis: Since limited data suggest that bisoprolol fumarate is not dialyzable, dose adjustment is unnecessary for dialysis patients. Hepatic Impairment: Hypertension or chronic, stable angina patients with severe liver impairment: Initial dose 2.5 mg orally once a day; if needed, titrated upward slowly, use with caution. Renal or hepatic impairment with chronic heart failure: There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

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