Metoprolol Tartrate (Page 4 of 6)

8.5 Geriatric Use

Clinical studies of metoprolol tartrate tablets in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.

In worldwide clinical trials of metoprolol tartrate tablets in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients.

In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

No studies have been performed with metoprolol tartrate tablets in patients with hepatic impairment. Because metoprolol tartrate tablets are metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.

8.7 Renal Impairment

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. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Signs and Symptoms – Overdosage of metoprolol tartrate tablets 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.

Treatment – Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures.

Hemodialysis is unlikely to make a useful contribution to metoprolol elimination [see Clinical Pharmacology (12.3)] .

Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs or pacemaker to treat bradycardia and conduction disorders.

Hypotension: 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 α1 receptor agonistic drugs added in presence of vasodilation.

Bronchospasm: Can usually be reversed by bronchodilators.

11 DESCRIPTION

Metoprolol tartrate tablets, USP contain metoprolol tartrate, a selective beta 1 -adrenoreceptor blocking agent. Metoprolol tartrate is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is

Metoprolol Tartrate Structural Formula
(click image for full-size original)

Metoprolol tartrate, USP is a white, crystalline powder with a molecular weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.

Metoprolol tartrate tablets, USP are available as 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg tablets for oral administration containing 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg metoprolol tartrate, respectively.

Inactive Ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, titanium dioxide and triacetin. The 37.5 mg tablets also contain FD&C Blue No. 2 Aluminum Lake. The 50 mg tablets also contain FD&C Blue No. 2 Aluminum Lake, D&C Red No. 27 Aluminum Lake and FD&C Red No. 40 Aluminum Lake. The 100 mg tablets also contain FD&C Blue No. 2 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metoprolol is a beta 1 -selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta 2 -adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.

The relative beta 1 -selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta 2 -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 FEV 1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta 1 -receptor blocking doses.

Hypertension

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.

Angina Pectoris

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.

Heart Failure

The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.

12.2 Pharmacodynamics

Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, 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 relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta 1 -blocking effects in the range of 30-80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30 to 540 nmol/L. The relative beta 1 -selectivity of metoprolol diminishes and blockade of beta 2 -adrenoceptors increases at plasma concentration above 300 nmol/L.

Significant beta-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 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. When the drug was infused over a 10-minute period, in normal volunteers, maximum beta-blockade was achieved at approximately 20 minutes. Equivalent maximal beta-blocking effect is achieved with oral and intravenous 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, intravenous followed by oral administration of metoprolol tartrate tablets 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.

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