Chemical Name:Metoprolol Succinate
Therapeutic Category:Cardiovascular drugs
Pharmacologic Category:Beta-Blocker, Beta-1 Selective
Composition:Metoprolol Succinate 50mg
Extended Release Film coated Tablets
MOPROL 25XR - XR/F.C.Tablets: Each Extended Release Film coated Tablets contains 23.75mg metoprolol Succinate equivalent to 25mg metoprolol tartrate.
MOPROL 50XR - XR/F.C.Tablets: Each Extended Release Film coated Tablets contains 47.5mg metoprolol Succinate equivalent to 50mg metoprolol tartrate.
MOPROL 100XR - XR/F.C.Tablets: Each Extended Release Film coated Tablets contains 95mg metoprolol Succinate equivalent to 100mg metoprolol tartrate.
MOPROL 200XR – XR/F.C.Tablets: Each Extended Release Film coated Tablets contains 190mg metoprolol Succinate equivalent to 200mg metoprolol tartrate.
Silicon Dioxide, Sodium Stearyl Fumarate, Polyethylene Glycols, Titanium Dioxide, Paraffin, Hypromelloses.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent, at higher plasma concentrations, metoprolol also inhibits beta2 -adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. The relative beta1 -selectivity of metoprolol has been confirmed by the following: (1) metoprolol is unable to reverse the beta2 -mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1 -receptor blocking doses.
3-MECHANISM of ACTION:
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Only a small fraction of the drug (about 12%) is bound to human serum albumin, and metabolized predominantly by CYP2D6. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. In comparison to conventional metoprolol, the plasma metoprolol levels following administration of METOPROLOL XR are characterized by lower peaks, longer time to peak.
METOPROLOL XR is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
METOPROLOL XR is indicated in the long-term treatment of angina pectoris.
METOPROLOL XR is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin.
METOPROLOL XR is contraindicated in case of:
-heart block greater than first degree,
-cardiogenic shock, de-compensated cardiac failure,
-sick sinus syndrome (unless a permanent pacemaker is in place).
-in patients who are hypersensitive to any component of this product.
Ischemic Heart Disease:
When discontinuing chronically administered METOPROLOL XR, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue METOPROLOL XR therapy abruptly even in patients treated only for hypertension.
Worsening cardiac failure may occur during up-titration of METOPROLOL XR. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of METOPROLOL XR.
Because of its relative beta1 -selectivity, however, METOPROLOL XR may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 -selectivity is not absolute, a beta2 -stimulating agent should be administered concomitantly, and the lowest possible dose of METOPROLOL XR should be used.
If METOPROLOL -XR is used in the setting of pheochromocytoma, it should be given in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Chronically administered beta-blocking therapy should not be routinely withdrawn; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia:
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.
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.
Calcium Channel Blockers:
Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
- Catecholamine depleting drugs (eg, reserpine, mono amine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Patients treated with METOPROLOL XR plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
- Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration, and increase the metoprolol elimination half-life when given with beta-blocking agents. These increases in plasma concentration would decrease the cardioselectivity of metoprolol
- 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 the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
Calcium Channel Blockers: Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
10-PREGNANCY, Category C:
There are no adequate and well-controlled studies in pregnant women.
Metoprolol is excreted in breast milk in very small quantities. Caution should be exercised when METOPROLOL XR is administered to a nursing woman.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
13-RISK OF ANAPHYLACTIC REACTIONS:
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction
Most adverse effects have been mild and transient.
Hypertension and Angina, Tiredness, dizziness, depression, mental confusion, short-term memory, headache, somnolence, nightmares, and insomnia, Shortness of breath, bradycardia, cold extremities, arterial insufficiency, palpitations, congestive heart failure, peripheral edema, syncope, chest pain, and hypotension, Wheezing (bronchospasm) and dyspnea, Diarrhea, nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, and heartburn, Pruritus, Worsening of psoriasis.
Peyronie's disease, musculoskeletal pain, blurred vision, decreased libido, tinnitus, bradycardia, myocardial infarction, pneumonia, cerebrovascular disorder, syncope, coronary artery disorder, ventricular tachycardia/arrhythmia aggravated.
Signs and Symptoms:
Overdosage of METOPROLOL XR may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.
the following general measures should be employed:
Evaluate the need for atropine, adrenergic-stimulating drugs or pacemaker to treat bradycardia and conduction disorders.
Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.
Heart failure and shock: May be treated when appropriate with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with α receptor agonistic drugs added in presence of vasodilation.
Can usually be reversed by bronchodilators.
16-DOSAGE and ADMINISTRATION:
This product is an extendedrelease tablet intended for once daily administration, when switching from immediate release metoprolol to METOPROLOL XR, the same total daily dose of METOPROLOL XR should be used.
Patients should be advised to take METOPROLOL XR regularly and continuously, as directed, preferably with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue METOPROLOL XR without consulting the physician. METOPROLOL XR tablets are scored and can be divided; however, the whole or half tablet should be swallowed whole and not chewed or crushed.
The usual initial dosage is 25 to 100 mg daily in a single dose, whether used alone or added to a diuretic. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy.
Pediatric Hypertensive Patients ≥ 6 Years of age:
The recommended starting dose of METOPROLOL XR is 1 mg/kg once daily, but the maximum initial dose should not exceed 50mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2mg/kg (or in excess of 200mg) once daily have not been studied in pediatric patients METOPROLOL XR is not recommended in pediatric patients < 6 years of age.
The dosage of METOPROLOL XR should be individualized. The usual initial dosage is 100mg daily, given in a single dose. The dosage may be gradually increased at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate, if treatment is to be discontinued, the dosage should be reduced gradually over a period of 1-2 weeks.
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of METOPROLOL XR, the dosing of diuretics, ACE inhibitors, and digitalis (if used) should be stabilized. The recommended starting dose of METOPROLOL XR is 25mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5mg once daily in patients with more severe heart failure. The dose should then be doubled every two weeks to the highest dosage level tolerated by the patient or up to 200mg of METOPROLOL XR.
MOPROL 25 XR - XR/F.C.Tablets: Carton package of 30 Extended Release Film coated Tablets in blister.
MOPROL 50 XR - XR/F.C.Tablets: Carton package of 30 Extended Release Film coated Tablets in blister.
MOPROL 100 XR - XR/F.C.Tablets: Carton package of 30 Extended Release Film coated Tablets in blister.
MOPROL 200 XR - XR/F.C.Tablets: Carton package of 30 Extended Release Film coated Tablets in blister.
Store MOPROL XR - XR/F.C.Tablets at 25°C. Excursions permitted to 15-30°C.