displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Metoprolol Tartrate Injection USP is a selective beta1-adrenoreceptor blocking agent, available in 5 mL vials for intravenous administration. Each vial contains a sterile solution of metoprolol tartrate, 5 mg, sodium chloride, 45 mg, and water for injection. Metoprolol tartrate is (±)-1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanoI L-(+)-tartrate (2:1) (salt), and its structural formula is:
Molecular Formula: (C15H25NO3)2•C4H6O6
Metoprolol tartrate is a white, practically odorless, crystalline powder with a molecular weight of 684.83. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. The pH range is 5.0 to 8.0.
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol tartrate also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.
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.
Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, metoprolol tartrate is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol tartrate reduces FEV1 and FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Metoprolol tartrate has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Metoprolol tartrate crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that metoprolol tartrate slows the sinus rate and decreases AV nodal conduction.
In controlled clinical studies, metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100 to 450 mg daily. In controlled, comparative, clinical studies, metoprolol tartrate has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions.
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 tartrate 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, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In controlled clinical trials, metoprolol tartrate, administered two or four times daily, has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. A controlled, comparative, clinical trial showed that metoprolol tartrate was indistinguishable from propranolol in the treatment of angina pectoris.
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol tartrate was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction.
Patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous followed by oral administration of metoprolol tartrate or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with metoprolol tartrate or placebo was then continued for 3 months. After this double-blind period, all patients were given metoprolol tartrate and followed up to 1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the metoprolol tartrate and placebo treatment groups. Among patients treated with metoprolol tartrate, there were comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with metoprolol tartrate and were independent of the interval between onset of symptoms and initiation of therapy.
The precise mechanism of action of metoprolol tartrate in patients with suspected or definite myocardial infarction is not known.
In this study, patients treated with metoprolol received the drug both very early (intravenously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. Because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta blockers.
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Metoprolol Tartrate Injection USP is supplied in 5 mL vials, each mL contains 1 mg metoprolol tartrate. NDC 54868-5726-0, cartons of 10.
Store at 20° to 25°C (68° to 77°F). See USP controlled room temperature. Do not freeze. Protect from light. Retain in carton until time of use. Discard unused portion.
To report SUSPECTED ADVERSE REACTIONS, contact Bedford Laboratories at
1-800-521-5169 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
PRINCIPAL DISPLAY PANEL
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
Metoprolol Tartrate Injection USP
5 mg/ 5 mL