Prescription Drug Name:

Metoprolol Tartrate Injection, USP, Rx only, Prescribing Information

ID:

47e20cb8-c2be-42cb-aeef-13d403ecb693

Code:

34391-3

DESCRIPTION


id: eb851a32-4931-46e0-bf0b-191b4168dd1d
displayName: Description Section
FDA Article Code: 34089-3

Metoprolol tartrate 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 USP, 5 mg, and sodium chloride USP, 45 mg, and water for injection USP.
Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L- (+)-tartrate (2:1) salt, and its structural formula is

Metoprolol tartrate USP is a white, practically odorless, 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.

CLINICAL PHARMACOLOGY


id: 2e5a615b-f009-4e28-83a9-93a8cf250ec3
displayName: Clinical Pharmacology Section
FDA Article Code: 34090-1

Mechanism of Action:
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have demonstrated 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.
Hypertension
The mechanism of the antihypertensive effects of beta-blocking agents has not been fully 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.
Myocardial Infarction
The precise mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known.
Pharmacodynamics
Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, metoprolol is able 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 reduces FEV1 and FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.
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.
In several studies of patients with acute myocardial infarction, intravenous 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.
Pharmacokinetics


Absorption:
The estimated oral bioavailability of immediate release metoprolol is about 50% because of pre-systemic metabolism which is saturable leading to non-proportionate increase in the exposure with increased dose.

Distribution:
Metoprolol is extensively distributed with a reported volume of distribution of 3.2 to 5.6 L/kg. About 10% of metoprolol in plasma is bound to serum albumin. Metoprolol is known to cross the placenta and is found in breast milk. Metoprolol is also known to cross the blood brain barrier following oral administration and CSF concentrations close to that observed in plasma have been reported. Metoprolol is not a significant P-glycoprotein substrate

Metabolism:
Metoprolol is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of R- and S- enantiomers, and when administered orally, it exhibits stereo selective metabolism that is dependent on oxidation phenotype. CYP2D6 is absent (poor metabolizers) in about 8% of Caucasians and about 2% of most other populations. Poor CYP2D6 metabolizers exhibit several- fold higher plasma concentrations of metoprolol than extensive metabolizers with normal CYP2D6 activity thereby decreasing metoprolol’s cardioselectivity.

Elimination:
Elimination of metoprolol is mainly by biotransformation in the liver. The mean elimination half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life may be 7 to 9 hours. Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolizers), less than 10% of an intravenous dose are excreted as unchanged drug in the urine. In poor metabolizers, up to 30% or 40% of oral or intravenous doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity. The renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion.
Special populations


Geriatric patients:
The geriatric population may show slightly higher plasma concentrations of metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically relevant.

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. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.

Hepatic Impairment:
Since the drug is primarily eliminated by hepatic metabolism, hepatic impairment may impact the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h).
Clinical Studies:

Hypertension
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 oral dosages of 100 to 450 mg daily. In controlled, comparative, clinical studies, metoprolol has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, to be equally effective in supine and standing positions.
Angina Pectoris
In controlled clinical trials, metoprolol, administered orally 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 oral dosage used in these studies ranged from 100 to 400 mg daily. A controlled, comparative, clinical trial showed that metoprolol was indistinguishable from propranolol in the treatment of angina pectoris.
Myocardial Infarction
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol 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 or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with metoprolol or placebo was then continued for 3 months. After this double-blind period, all patients were given metoprolol and followed up to1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the metoprolol – and placebo-treatment groups. Among patients treated with metoprolol, 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 and were independent of the interval between onset of symptoms and initiation of therapy.
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.

INDICATIONS & USAGE


id: 8b775081-1979-400a-9696-c66b2ff234d2
displayName: Indications & Usage Section
FDA Article Code: 34067-9

Myocardial Infarction
Metoprolol Tartrate Injection USP, vials are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. Treatment with intravenous metoprolol can be initiated as soon as the patient’s clinical condition allows (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS).

CONTRAINDICATIONS


id: b4044c90-1a73-4017-a6d9-e9d99c45ef6e
displayName: Contraindications Section
FDA Article Code: 34070-3

Hypersensitivity to metoprolol and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur).
Myocardial Infarction
Metoprolol is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure <100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).

WARNINGS


id: 52676c33-74ae-4663-95ee-42ecf60838ba
displayName: Warnings Section
FDA Article Code: 34071-1

Heart Failure
Beta blockers, like metoprolol, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient according to recommended guidelines. It may be necessary to lower the dose of metoprolol or to discontinue it.
Ischemic Heart Disease
Do not abruptly discontinue metoprolol therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with beta-blockers. When discontinuing chronically administered metoprolol, particularly in patients with coronary artery disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. 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.
Use During Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Bradycardia

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving metoprolol. If severe bradycardia develops, reduce or stop metoprolol.
Exacerbation of Bronchospastic Disease
Patients with bronchospastic disease, should, in general, not receive beta blockers, including metoprolol. Because of its relative beta1 selectivity, however, metoprolol may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1 selectivity is not absolute use the lowest possible dose of metoprolol and consider administering metoprolol in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION). Bronchodilators, including beta2 agonists, should be readily available or administered concomitantly.
Diabetes and Hypoglycemia
Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Pheochromocytoma
If metoprolol 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.
Thyrotoxicosis
Metoprolol may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.

ADVERSE REACTIONS


id: 49700441-8ead-4737-a163-ed79c3482384
displayName: Adverse Reactions Section
FDA Article Code: 34084-4

 Hypertension and Angina
These adverse reactions were reported for treatment with oral metoprolol. Most adverse effects have been mild and transient.

Central Nervous System:
Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported.

Cardiovascular:
Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)

Respiratory:
Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see WARNINGS). Rhinitis has also been reported.

Gastrointestinal:
Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.

Hypersensitive Reactions:
Pruritus or rash have occurred in about 5 of 100 patients. Very rarely,photosensitivity and worsening of psoriasis has been reported.

Miscellaneous:
Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Musculoskeletal pain, blurred vision, and tinnitus have also been reported.There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes.
Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to metoprolol has not been definitely established).e oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with metoprolol.
Myocardial Infarction
These adverse reactions were reported from treatment regimens where intravenous metoprolol was administered, when tolerated.

Central Nervous System:
Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear.

Cardiovascular:
In the randomized comparison of metoprolol and placebo described in the CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:

  Metoprolol

Placebo

Hypotension (systolic BP <90 mmHg) 27.4% 23.2%
Bradycardia (heart rate <40 beats/min) 15.9% 6.7%
Second- or third-degree heart block 4.7% 4.7%
First-degree heart block (P-R ≥0.26 sec) 5.3% 1.9%
Heart failure 27.5% 29.6%

Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
Gastrointestinal: Nausea and abdominal pain have been reported in less than 1 of 100 patients.
Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not clear.
Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is not clear.
Potential Adverse Reactions A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of metoprolol: confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

OVERDOSAGE


id: f9eaa658-6605-4679-8ab3-d518868aa3ee
displayName: Overdosage Section
FDA Article Code: 34088-5

Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms
Potential signs and symptoms associated with overdosage with metoprolol are bradycardia, hypotension, bronchospasm, myocardial infarction, cardiac failure and death.
Management
There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial Infarction).
On the basis of the pharmacologic actions of metoprolol, the following general measures should be employed:

Elimination of the Drug:
Gastric lavage should be performed.
Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.

Hypotension:
Administer a vasopressor, e.g., levarterenol or dopamine.

Bronchospasm:
Administer a beta2-stimulating agent and/or a theophylline derivative.

Cardiac Failure:
Administer digitalis glycoside and diuretic. In shock resulting from inadequate cardiac contractility, consider administration of dobutamine, isoproterenol or glucagon.

DOSAGE & ADMINISTRATION


id: 676e8816-b654-433e-b6f0-fbad3c8f7838
displayName: Dosage & Administration Section
FDA Article Code: 34068-7

 Myocardial Infarction

Early Treatment:
During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol 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.
Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of metoprolol each; give the injections at approximately 2-minute intervals. During the intravenous administration of metoprolol, monitor blood pressure, heart rate, and electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the maintenance dosage is 100 mg orally twice daily.
Start patients who appear not to tolerate the full intravenous dose on metoprolol tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance, discontinue metoprolol (see WARNINGS).
Special populations

Pediatric patients:
No pediatric studies have been performed. The safety and efficacy of metoprolol in pediatric patients have not been established.

Renal impairment:
No dose adjustment of metoprolol is required in patients with renal impairment.

Hepatic impairment:
metoprolol blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, metoprolol should be initiated at low doses with cautious gradual dose titration according to clinical response.

Geriatric patients (>65 years):
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.
Method of administration:
Parenteral administration of metoprolol vial should be done in a setting with intensive monitoring.

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

HOW SUPPLIED


id: f76b600c-1ca4-4dc9-a799-98b0e46a1dce
displayName: How Supplied Section
FDA Article Code: 34069-5

Metoprolol Tartrate Injection, USP is supplied as follows:
 

NDC

Metoprolol Tartrate Injection, USP
(1 mg per 1 mL)

Package Factor

68083-131-01 5 mg per 5mL Single-Dose Vial 10 vials per carton

Storage Conditions:
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59°-86°F). [See USP Controlled Room Temperature]. Protect from light and heat.
Do not freeze. Retain in carton until time of use.
To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Manufactured by:
Gland Pharma Limited
D.P.Pally, Dundigal Post
Hyderabad-500 043, INDIA.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


id: 7e7d8694-af50-4072-8714-0ed212593fb2
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

Metoprolol Tatrate Injection, USP
5 mg per 5 mL (1 mg/mL)
Rx only
For Intravenous use.
Vial Label