Betaloc (Metoprolol Tartrate)



Metoprolol Tartrate

b-Adrenoceptor Blocking Agent

Action And Clinical Pharmacology: Metoprolol is a b-adrenoceptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on b1-adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol also inhibits b2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. It is used in the treatment of hypertension, angina pectoris and to reduce mortality in patients with myocardial infarction.

The mechanism of the antihypertensive effect has not been established. Among the factors that may be involved are: competitive ability to antagonize catecholamine-induced tachycardia at the beta-receptor sites in the heart, thus decreasing heart rate, cardiac contractility and cardiac output; inhibition of renin release by the kidneys; inhibition of the vasomotor centres.

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. However, in patients with heart failure, b-adrenoceptor blockade may increase oxygen requirements by increasing left ventricular fibre length and end-diastolic pressure.

The mechanisms involved in reducing mortality in patients with acute myocardial infarction are not fully understood.

Pharmacokinetics: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following i.v. administration, indicating about 50% first-pass metabolism.

Intersubject plasma levels achieved are highly variable after oral administration, although they show good reproducibility within each individual. Peak plasma concentrations are attained after approximately 1.5 to 2 hours with conventional metoprolol formulations, and after approximately 4 to 5 hours with sustained-release formulations. Upon repeated oral administration, the percentage of the dose systemically available is higher than after a single dose and also increases dose-dependently. Ingestion together with food may raise the systemic availability of an oral dose by approximately 30 to 40%. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Elimination is mainly by biotransformation in the liver, and the plasma half-life averages 3.5 hours (extremes: 1 and 9 hours). The total clearance rate is approximately 1 L/min and the protein binding rate is approximately 5 to 10%. 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 clinical significance.

The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. The excretion of metabolites, however, is reduced. Significant accumulation of metabolites was observed in patients with a GFR of approximately 5 mL/min, but this accumulation does not influence the b-blocking effects of metoprolol. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.

Elderly subjects show no significant changes in the plasma concentrations of metoprolol as compared with young persons. However, plasma concentrations of the major pharmacologically active metabolites were higher in the elderly.

Liver cirrhosis may increase the bioavailability of metoprolol and reduce its total clearance.

Pharmacodynamics: Significant b-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50 and 100 mg occurred at 3.3, 5.0 and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.

Following i.v. administration of metoprolol, the half-life of the distribution phase is approximately 12 minutes; the urinary recovery of unchanged drug is approximately 10%. When the drug was infused over a 10 minute period, in normal volunteers, maximum b-blockade was achieved at approximately 20 minutes. Doses of 5 and 15 mg yielded a maximal reduction in exercise-induced heart rate of approximately 10 and 15%, respectively. The effect on exercise heart rate decreased linearly with time at the same rate for both doses, and disappeared at approximately 5 hours and 8 hours for the 5 mg and 15 mg doses, respectively.

Equivalent maximal beta-blocking effect is achieved with oral and i.v. doses in the ratio of approximately 2.5:1.

There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.

In several studies of patients with acute myocardial infarction, i.v. followed by oral administration of metoprolol caused a reduction in heart rate, systolic blood pressure and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged.

Studies in hypertensive and angina patients have shown plasma levels of 28 to 46 ng/mL 12 hours after regular tablets and 19 to 45 ng/mL 24 hours after Durules and were comparable to the peak levels after 100 mg regular tablets.

Indications And Clinical Uses: Hypertension: In patients with mild or moderate hypertension. It may be used alone or in combination with other antihypertensive agents (see Dosage).

The combination of metoprolol with a diuretic or peripheral vasodilator has been found to be compatible and generally more effective than metoprolol alone. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with metoprolol.

Not recommended for the emergency treatment of hypertensive crises.

Angina Pectoris: For the long-term treatment of angina pectoris due to ischemic heart disease.

Myocardial Infarction: In the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality.

Treatment with i.v. metoprolol can be initiated as soon as the patient’s clinical condition allows (see Dosage, Contraindications and Warnings). Alternatively, in patients with proven myocardial infarction, oral treatment can begin within 3 to 10 days of the acute event (see Dosage). Data are not available as to whether benefit would ensue if the treatment is initiated later.

Clinical trials have shown that patients in whom the myocardial infarction was unconfirmed, received no benefit from early metoprolol therapy.

Contra-Indications: Known hypersensitivity to metoprolol and related derivatives; sinus bradycardia; sick sinus syndrome; second- and third-degree AV block; right ventricular failure secondary to pulmonary hypertension; overt heart failure; cardiogenic shock; severe peripheral arterial circulatory disorders; anesthesia with agents that produce myocardial depression, e.g. ether. The i.v. form is also contraindicated in the presence of asthma and other obstructive respiratory diseases (for oral treatment, see Precautions, Bronchospastic Diseases).

Manufacturers’ Warnings In Clinical States: Cardiac Failure: Special caution should be exercised when administering metoprolol to patients with a history of heart failure. 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. The positive inotropic action of digitalis may be reduced by the negative inotropic effect of metoprolol when the two drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing AV conduction. This also applies to combinations with calcium antagonists of the verapamil type or some antiarrhythmics (see Precautions, Drug Interactions).

In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure and/or hypotension (systolic blood pressure£90 mmHg). Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, therapy should be reduced or withdrawn.

Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of metoprolol. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy. The last 2 complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation is planned in patients with angina pectoris or previous myocardial infarction, the dosage should be gradually reduced over a period of at least 10 to 14 days, in diminishing doses, to 25 mg once a day for the last 6 days. During this period the patient should be carefully observed. In situations of greater urgency, metoprolol therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with metoprolol should be reinstituted promptly, at least temporarily.

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 therapy abruptly even in patients treated only for hypertension.

Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including metoprolol. Oculomucocutaneous syndrome, a severe syndrome whose signs include conjunctivitis sicca and psoriasiform rashes, otitis and sclerosing serositis, has occurred with chronic use of one b-adrenergic-blocking agent (practolol). This syndrome has not been observed with metoprolol 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.

Severe Sinus Bradycardia: Severe sinus bradycardia may occur with the use of metoprolol from unopposed vagal activity remaining after blockade of b1-adrenergic receptors. Very rarely a pre-existing AV conduction disorder of moderate degree may become aggravated, possibly leading to AV block. In such cases, dosage should be reduced. Atropine, isoproterenol or dobutamine should be considered in patients with acute myocardial infarction.

Thyrotoxicosis: Although metoprolol has successfully been used for the symptomatic (adjuvant) therapy of thyrotoxicosis, possible deleterious effects from long-term use of metoprolol have not been adequately appraised. b-blockade may mask the clinical signs of continuing hyperthyroidism or complications and give a false impression of improvement. Therefore, abrupt withdrawal of metoprolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

Myocardial Infarction Patients: Additional Warnings: Acute Intervention: During acute intervention in myocardial infarction, i.v. metoprolol should only be used by experienced staff under circumstances where resuscitation and monitoring equipment are available.

Cardiac Failure: Depression of the myocardium with metoprolol may lead to cardiac failure (see general Warnings). Special caution should be exercised when administering metoprolol to patients with a history of cardiac failure or those with a minimal cardiac reserve. Should failure occur, treatment should be as described in Warnings.

Severe Sinus Bradycardia: See general Warnings for severe sinus bradycardia.

AV Conduction: Metoprolol slows AV conduction and may produce significant first- (PR interval ³ 0.26 s), second-, or third-degree heart block. Acute myocardial infarction also produces heart block.

If heart block occurs, metoprolol should be discontinued and atropine (0.25 to 0.5 mg) should be administered i.v. If treatment with atropine is not successful, cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.

Hypotension: If hypotension (systolic blood pressure £90 mmHg) occurs, metoprolol should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required. Appropriate therapy with fluids, positive inotropic agents, balloon counterpulsation, or other treatment modalities should be instituted. If hypotension is associated with sinus bradycardia or AV block, treatment should be directed at reversing these (see above).

Precautions: Bronchospastic Diseases: Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative b1-selectivity, however, metoprolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since b1-selectivity is not absolute, a b2-stimulating agent should preferably be administered concomitantly, and the lowest possible dose of metoprolol should be used. In these circumstances it would be prudent initially to administer metoprolol in smaller doses 3 times daily, instead of larger doses 2 times daily, to avoid the higher plasma levels associated with the longer dosing interval (see Dosage).

Because it is unknown to what extent b2-stimulating agents may exacerbate myocardial ischemia and the extent of infarction, these agents should not be used prophylactically in patients with proven or suspected acute myocardial infarction. If bronchospasm not related to congestive heart failure occurs, metoprolol should be discontinued. A theophylline derivative or a b2-agonist may be administered cautiously, depending on the clinical condition of the patient. Both theophylline derivatives and b2-agonists may produce serious cardiac arrhythmias.

Diabetes and Hypoglycemia: Metoprolol should be administered with caution to diabetic patients subject to spontaneous hypoglycemia (most of these patients are insulin treated). b-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia, but this is mainly attributed to unselective b-adrenergic blockers.

Liver Function: Metoprolol should be used with caution in patients with impaired liver function. Liver function tests should be performed at regular intervals during long-term treatment. Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has low protein binding (5 to 10%). When there are signs of serious impairment of liver function (e.g., shunt-operated patients) a dose reduction should be considered.

Allergen Immunotherapy: There may be increased difficulty in treating an allergic type reaction in patients on b-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the b-blockers and 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 b-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.

Patients Undergoing Surgery: It is not advisable to withdraw b-adrenoceptor blocking drugs prior to surgery in the majority of patients especially in those with risk of overt or silent coronary heart disease. However, care should be taken to avoid using anesthetic agents that may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg i.v.).

Some patients receiving b-blocking drugs have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.

Since metoprolol is a competitive inhibitor of b-adrenoceptor agonists, its effects may be reversed, if necessary, by sufficient doses of such antagonists as isoproterenol or dobutamine.

Peripheral Artery Disorders: Metoprolol may aggravate the symptoms of peripheral arterial circulatory disorders, mainly due to its blood pressure lowering effect.

Pheochromocytoma: Where a b-blocker is prescribed for a patient known to be suffering from a pheochromocytoma, an a-blocker should be given concomitantly.

Occupational Hazards: Reaction Time: b-blockers may adversely affect the patient’s reaction time. Patients should be advised to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol has been determined.

Pregnancy: Metoprolol crosses the placental barrier. Since metoprolol has not been studied in human pregnancy, it should not be given to pregnant women. The use of any drug in patients of child-bearing potential requires that the anticipated benefit be weighed against possible hazards.

Lactation: Metoprolol is excreted in breast milk in very small quantities. Caution should be exercised when metoprolol is administered to a nursing woman.

Children: The safety and efficacy of metoprolol in children has not been established.

Geriatrics: Caution is indicated when using metoprolol in elderly patients. An excessively pronounced decrease in blood pressure or pulse rate may cause the blood supply to vital organs to fall to inadequate levels.

Drug Interactions: Antihypertensives: Dosage should be adjusted according to the individual requirements of the patient especially when used concomitantly with other antihypertensive agents (see Dosage).

MAO Inhibitors and Adrenergic Neuron Blockers: Patients receiving MAO inhibitors or catecholamine-depleting drugs, (such as reserpine or guanethidine), should be closely monitored because the added b-adrenergic-blocking action of metoprolol may produce an excessive reduction of sympathetic activity. Metoprolol should not be combined with other b-blockers.

Calcium Entry Blockers: As with other b-blockers metoprolol should not be given to patients receiving calcium antagonists of the verapamil type. However, in exceptional cases, when in the opinion of the physician concomitant use is considered essential, such use should be instituted gradually in a hospital setting under careful supervision. Negative inotropic, dromotropic, and chronotropic effects may occur when metoprolol is given together with calcium antagonists. Verapamil and diltiazem may reduce clearance of metoprolol.

Antiarrhythmic Agents: b-blockers may enhance the negative inotropic and negative dromotropic effect of antiarrhythmic agents such as quinidine and amiodarone.

Clonidine Withdrawal Syndrome: The hypertensive crisis which may follow the withdrawal of clonidine may be accentuated in the presence of b-blockade. It has been proposed that withdrawal of the b-blocker several days before the clonidine may reduce the danger of rebound effects.

Oral Antidiabetics: The dosage of oral antidiabetics may have to be readjusted in patients receiving b-blockers (see Precautions).

Indomethacin: Concurrent treatment with indomethacin may decrease the antihypertensive effect of b-blockers.

Hepatic Enzyme-Inducers and Enzyme-Inhibitors: Hepatic enzyme-inducing and enzyme-inhibiting substances may exert an influence on the plasma level of metoprolol. The plasma concentration of metoprolol is lowered by rifampin, and may be raised by cimetidine, ranitidine, propafenone and hydralazine.

Lidocaine: Metoprolol may reduce the clearance of lidocaine.

Adverse Reactions: Adverse reactions have generally been mild and reversible. The following events have been reported as adverse events in clinical trials or reported from routine use. In many cases, a relationship to treatment with metoprolol has not been established.

The most common adverse events reported are exertional tiredness, gastrointestinal disorders and disturbances of sleep patterns. The most serious adverse events reported are congestive heart failure, bronchospasm and hypotension.

Reported adverse events according to organ systems are: Cardiovascular: congestive heart failure (see Warnings); secondary effects of decreased cardiac output, which include: syncope, vertigo, lightheadedness and postural hypotension; severe bradycardia; lengthening of PR interval; second and third degree AV block; sinus arrest; cardiac arrhythmias; palpitations; chest pains; edema; cold extremities; claudication; gangrene in patients with pre-existing severe peripheral circulatory disorders; hot flushes.

CNS: headache, dizziness, mental depression, lightheadedness, concentration impaired, anxiety, weakness, fatigue, sedation, somnolence or insomnia, vivid dreams/nightmares, vertigo, paresthesia, hallucination, nervousness, impotence/sexual dysfunction, amnesia/memory impairment, confusion.

Gastrointestinal: diarrhea, constipation, flatulence, heartburn, nausea and vomiting, abdominal pain, dryness of mouth, hepatitis.

Respiratory: shortness of breath, wheezing, bronchospasm, status asthmaticus, rhinitis.

Allergic/Dermatological (see Warnings): skin rash (exanthema, urticaria, psoriasiform and dystrophic skin lesions); sweating; pruritus; photosensitivity.

Eye, Ear, Nose and Throat (EENT): blurred vision and non-specific visual disturbances; dry and/or itching eyes; conjunctivitis; tinnitus; hearing difficulties in doses exceeding those recommended; taste disturbances.

Miscellaneous: muscle cramps; exertional tiredness; weight gain; loss of hair; arthritis; Peyronie’s disease.

Clinical Laboratory: The following laboratory parameters have been rarely elevated: transaminases, BUN, alkaline phosphatase and bilirubin. Isolated cases of thrombocytopenia and leukopenia have been reported.

Symptoms And Treatment Of Overdose: Symptoms: The most common signs to be expected with overdosage of a b-adrenoceptor blocking agent are hypotension, bradycardia, congestive heart failure, bronchospasm and hypoglycemia. Atrioventricular block, cardiogenic shock and cardiac arrest may develop. In addition, impairment of consciousness (or even coma), nausea, vomiting and cyanosis may occur.

Concomitant ingestion of alcohol, antihypertensives, quinidine, or barbiturates aggravate the signs and symptoms.

The first manifestations of overdosage set in 20 minutes to 2 hours after drug administration.

Treatment: If overdosage occurs, in all cases therapy with metoprolol should be discontinued and the patient hospitalized and observed closely. Remove any drug remaining in the stomach by induction of emesis or gastric lavage. In addition, if required, the following therapeutic measures are suggested.

Bradycardia and Hypotension: Initially 1 to 2 mg of atropine sulfate should be given i.v. If a satisfactory effect is not achieved, norepinephrine or dopamine may be administered after preceding treatment with atropine (see Precautions concerning the use of epinephrine in b-blocked patients). In case of hypoglycemia glucagon (1 to 10 mg) can also be administered.

Heart Block (second- or third-degree): Isoproterenol or transvenous cardiac pacemaker.

Congestive Heart Failure: Conventional therapy.

Bronchospasm: I.V. aminophylline or b2-agonist.

Hypoglycemia: I.V. glucose.

It should be remembered that metoprolol 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 metoprolol. However, the complications of excess isoproterenol e.g., hypotension and tachycardia, should not be overlooked.

Dosage And Administration: Hypertension: Metoprolol is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic, but may be used alone (see Indications).

The dose must always be adjusted to the individual requirements of the patient, in accordance with the following guidelines.

Metoprolol treatment should be initiated with doses of 50 mg b.i.d. If an adequate response is not seen after 1 week, dosage should be increased to 100 mg b.i.d. In some cases the daily dosage may need to be increased by further 100 mg increments at intervals of not less than 2 weeks up to a maximum of 200 mg b.i.d., which should not be exceeded. The usual maintenance dose is within the range of 100 to 200 mg daily.

When metoprolol is combined with another antihypertensive agent which is already being administered, metoprolol should be added initially at a dose of 50 mg b.i.d. After 1 or 2 weeks the daily dosage may be increased if required, in increments of 100 mg, at intervals of not less than 2 weeks, until adequate blood pressure control is obtained.

Angina pectoris: The recommended dosage range is 100 to 400 mg/day in divided doses.

Treatment should be initiated with 50 mg b.i.d. for the first week. If the response is inadequate, the daily dosage should be increased by 100 mg for the next week. The usual maintenance dose is 200 mg/day.

The need for further increases should be closely monitored at weekly intervals and the dosage increased in 100 mg increments to a maximum of 400 mg/day in 2 or 3 divided doses.

A metoprolol dose of 400 mg/day should not be exceeded.

Slow-release Durules: 200 mg slow-release tablets are intended only for maintenance dosing in those patients requiring doses of 100 to 400 mg/day. Treatment must always be initiated and individual titration of dosage carried out using the regular tablets. Dosing with half or whole Durules may be preferred for maintenance because of the convenience of once daily administration. One half Durules will provide 100 mg slow-release metoprolol. The following maintenance doses may now be accommodated: 100 mg is equal to one half Durules, 200 mg is equal to 1 Durules, 300 mg is equal to one and one half Durules, 400 mg is equal to 2 Durules.

*Extreme caution should be exercised when giving i.v. metoprolol to patients with heart rates between 45 and 60 and/or pulmonary rales less than 10 cm. Therapy should be discontinued in patients if the heart rate drops below 45 or the systolic blood pressure drops below 100 mmHg.

Early Treatment: During the early phase of definite or suspected acute myocardial infarction, treatment with metoprolol can be initiated as soon as possible after the patient’s arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized.

Treatment in this early phase should begin with the i.v. administration of 3 bolus injections of 5 mg each. The injections should be given at approximately 2 minute intervals. During the i.v. administration of metoprolol, blood pressure, heart rate, and electrocardiogram should be carefully monitored. If any of the injections are associated with adverse cardiovascular effects, i.v. administration should be stopped immediately and the patient should be observed carefully and appropriate therapy instituted.

In patients who tolerate the full i.v. dose (15 mg), metoprolol tablets, 50 mg every 6 hours should be initiated 15 minutes after the last i.v. dose and continued for 48 hours. Thereafter, patients should receive a maintenance dosage of 100 mg twice daily (see Late Treatment).

Patients who appear not to tolerate the full i.v. dose should be started on either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last i.v. dose or as soon as their clinical condition allows. In patients with severe intolerance, treatment with metoprolol should be discontinued (see Warnings).

Late Treatment (for proven myocardial infarction patients only): Patients with contraindications to treatment during the early phase of myocardial infarction, patients who appear not to tolerate the full early treatment, and patients in whom the physician wishes to delay therapy for any other reason should be started on metoprolol tablets, 100 mg twice daily, as soon as their clinical condition allows. Treatment can begin within 3 to 10 days of the acute event. Therapy should be continued for at least 3 months. Although the efficacy of treatment with metoprolol beyond 6 months has not been conclusively established, data from studies with other beta-blockers suggest that the treatment should be continued for 1 to 3 years.

Impaired Liver Function: Dose adjustment is normally not needed in patients suffering from liver cirrhosis because metoprolol has low protein binding (5 to 10%). When there are signs of serious impairment of liver function (e.g., shunt-operated patients) a dose reduction should be considered.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Availability And Storage: Tablets: 50 mg: Each compressed, white, scored, biconvex, circular tablet, contains: metoprolol tartrate 50 mg. Nonmedicinal ingredients: colloidal silica, lactose, magnesium stearate, microcrystalline cellulose, polyvinyl pyrrolidone and sodium starch glycolate. Energy: 0.31 kJ (0.07 kcal). Gluten- and tartrazine-free. Bottles of 100 and 500. Store at 15 to 30°C.

100 mg: Each compressed, white, scored, biconvex circular tablet, contains: metoprolol tartrate 100 mg. Nonmedicinal ingredients: colloidal silica, lactose, magnesium stearate, microcrystalline cellulose, polyvinyl pyrrolidone and sodium starch glycolate. Energy: 0.61 kJ (0.15 kcal). Gluten- and tartrazine-free. Bottles of 100 and 500. Store at 15 to 30°C.

Durules: Each white, biconvex rod-shaped film-coated tablet contains: metoprolol tartrate 200 mg. Nonmedicinal ingredients: aluminum silicate, ethylcellulose, hydroxypropyl methylcellulose, magnesium stearate, paraffin, polyethylene glycol and titanium dioxide. Gluten-, lactose- and tartrazine-free. Bottles of 100 and 500. Store at 15 to 30°C.

Injection: Each mL of aqueous injectable solution contains: metoprolol tartrate 1 mg. Also contains sodium chloride 45 mg (9 mg/mL). Glass vials of 5 mL. Store at 15 to 30°C, protected from light. (Shown in Product Recognition Section)

BETALOC® BETALOC® DURULES® Astra Metoprolol Tartrate b-Adrenoceptor Blocking Agent

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