Metoprolol Tartrate 100 MG Oral Tablet [Lopressor]
Generic Name: METOPROLOL TARTRATE
Brand Name: Lopressor
- Substance Name(s):
- METOPROLOL TARTRATE
DRUG INTERACTIONS
7 Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents.
( 7.1 ) Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
( 7.2 ) CYP2D6 Inhibitors are likely to increase metoprolol concentration.
( 7.3 ) Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia.
( 7.4 ) Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine.
( 7.4 ) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents.
Observe patients treated with LOPRESSOR plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
7.2 Epinephrine While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
7.3 CYP2D6 Inhibitors Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations.
While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration.
Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology ( 12.3 )].
Monitor patients closely, when the combination cannot be avoided.
7.
4 Negative Chronotropes Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate.
Concomitant use with beta-blockers can increase the risk of bradycardia.
If clonidine and a beta-blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine.
If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped .
OVERDOSAGE
10 Signs and Symptoms – Overdosage of LOPRESSOR 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 α 1 receptor agonistic drugs added in presence of vasodilation.
Bronchospasm: Can usually be reversed by bronchodilators.
DESCRIPTION
11 Lopressor tablets 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 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.
Lopressor is available as 50 mg and 100 mg tablets for oral administration containing 50 mg and 100 mg metoprolol tartrate, respectively.
Inactive Ingredients: Tablets contain microcrystalline cellulose, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate.
Film coating contains Opadry YS-1-1419 Pink (50 mg tablets) or Opadry YS-1-4281 Blue (100 mg tablets).
structural formula
CLINICAL STUDIES
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypertension and Angina Most adverse effects have been mild and transient.
Central Nervous System: Tiredness and dizziness have occurred in about 10% of 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 patients.
Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; heart failure exacerbations; peripheral edema; and hypotension have been reported in about 1% of patients.
Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported.
[see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] .
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1% of patients [see Warnings and Precautions ( 5.3 )] .
Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5% of patients.
Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1% of patients.
Vomiting was a common occurrence.
Hypersensitive Reactions: Pruritus or rash have occurred in about 5% of patients.
Photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease, musculoskeletal pain, blurred vision, and tinnitus has been reported.
Myocardial Infarction In general, the adverse reactions observed in trials with metoprolol in MI are consistent with the hypertension and angina experience.
In a randomized comparison of Lopressor and placebo in the setting of acute MI the following adverse reactions were reported: Lopressor ® Placebo Hypotension (systolic BP < 90 mm Hg) 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%
HOW SUPPLIED
16 /STORAGE AND HANDLING Lopressor ( metoprolol tartrate ) t ablets Tablets 50 mg – capsule-shaped, biconvex, pink, scored (imprinted LOPRESSOR on one side and 458 twice on the scored side) Bottles of 100………………………………………….………NDC 30698-458-01 Tablets 100 mg – capsule-shaped, biconvex, light blue, scored (imprinted LOPRESSOR on one side and 459 twice on the scored side) Bottles of 100………………………………………………….
NDC 30698-459-01 Storage: Store at 77°F (25°C); excursions permitted to 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature].
Protect from moisture and heat.
Dispense in a tight, light-resistant container (USP).
GERIATRIC USE
8.5 Geriatric Use Clinical studies of LOPRESSOR 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 Lopressor in myocardial infarction, where approximately 478 patients were over 65years 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.
DOSAGE FORMS AND STRENGTHS
3 LOPRESSOR is supplied as: 50 mg tablet – capsule shaped, biconvex, pink, scored (imprinted GEIGY on one side and 51 twice on the scored side) 100 mg tablet – capsule shaped, biconvex, light blue, scored (imprinted with GEIGY on one side and 71 twice on the scored side) LOPRESSOR (metoprolol tartrate) tablets: 50 mg and 100 mg.
( 3 )
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 IND ICATIONS AND USAGE LOPRESSOR is a beta-adrenergic blocker indicated for the treatment of: Hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.
( 1.1 ) Angina Pectoris.
( 1.2 ) Myocardial Infarction, to reduce the risk of cardiovascular mortality when used in conjunction with intravenous metoprolol therapy in patients with definite or suspected acute myocardial infarction in hemodynamically stable patients.
( 1.3 ) 1.1 Hypertension LOPRESSOR is indicated for the treatment of hypertension in adult patients, to lower blood pressure.
Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.
These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.
Many patients will require more than 1 drug to achieve blood pressure goals.
For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.
The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.
Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).
These considerations may guide selection of therapy.
LOPRESSOR may be administered with other antihypertensive agents.
1.2 Angina Pectoris LOPRESSOR is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.
1.3 Myocardial Infarction Lopressor tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in conjunction with intravenous metoprolol.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of LOPRESSOR have not been established in pediatric patients.
PREGNANCY
8.1 Pregnancy Risk Summary Available data from published observational studies have not demonstrated an association of adverse developmental outcomes with maternal use of metoprolol during pregnancy ( see Data).
Untreated hypertension and myocardial infarction during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations).
In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, approximately 11 times the daily dose of 450 mg in a 60-kg patient on a mg/m 2 basis.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical consideration Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
Pregnant women with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal adverse reactions Metoprolol crosses the placenta.
Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression.
Observe neonates and manage accordingly.
Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol in pregnancy.
The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation.
Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother.
These observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy.
Animal Data Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e., 11 times, on a mg/m 2 basis, the daily dose of 450 mg in a 60-kg patient.
No fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e., 4 times, the daily dose of 400mg in a 60-kg patient.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Abrupt cessation may exacerbate myocardial ischemia.
( 5.1 ) Heart Failure: Worsening cardiac failure may occur.
( 5.2 ) Bronchospastic Disease: Avoid beta-blockers.
( 5.3 ) Pheochromocytoma: Initiate therapy with an alpha blocker.
( 5.4 ) Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery.
Do not routinely withdraw chronic beta-blocker therapy prior to surgery.
( 5.5 , 6.1 ) Diabetes: May mask symptoms of hypoglycemia.
( 5.6 ) Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm.
( 5.7 ) Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency.
( 5.9 ) 5.1 Abrupt Cessation of Therapy Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred.
When discontinuing chronically administered LOPRESSOR, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient.
If angina markedly worsens or acute coronary ischemia develops, promptly reinstate LOPRESSOR, and take measures appropriate for the management of unstable angina.
Warn patients not to interrupt therapy without their physician’s advice.
Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing LOPRESSOR in patients treated only for hypertension.
5.2 Heart Failure Worsening cardiac failure may occur during up-titration of LOPRESSOR.
If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of LOPRESSOR [see Dosage and Administration ( 2 )].
It may be necessary to lower the dose of LOPRESSOR or temporarily discontinue it.
Such episodes do not preclude subsequent successful titration of LOPRESSOR.
5.3 Bronchospastic Disease Patients with bronchospastic disease, should in general, not receive beta-blockers, including Lopressor.
Because of its relative beta 1 cardio-selectivity, however, LOPRESSOR may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment.
Because beta 1 -selectivity is not absolute, use the lowest possible dose of LOPRESSOR.
Bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly [see Dosage and Administration ( 2 )].
5.4 Pheochromocytoma If LOPRESSOR 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.
5.5 Major Surgery Avoid initiation of a high-dose regimen of beta-blocker therapy in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.
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.
5.6 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting).
If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.
Beta-blockers may ask some of the manifestations of hypoglycemia, particularly tachycardia.
5.
7 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia.
Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
5.8 Risk of Anaphylactic Reactions While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
5.
9 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to take LOPRESSOR regularly and continuously, as directed, preferably with or immediately following meals.
If a dose is missed, the patient should take only the next scheduled dose (without doubling it).
Patients should not interrupt or discontinue LOPRESSOR without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with LOPRESSOR has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking LOPRESSOR.
Inform patients or caregivers that there is a risk of hypoglycemia when LOPRESSOR is given to patients who are fasting or who are vomiting.
Monitor for symptoms of hypoglycemia.
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DOSAGE AND ADMINISTRATION
2 Administer once daily with food or after a meal.
Titrate at weekly or longer intervals as needed and tolerated.
( 2 ) Hypertension: Recommended starting dosage is 100 mg daily, in single or divided doses.
( 2.1 ) Angina Pectoris: Recommended starting dosage is 100 mg daily, given as two divided doses.
( 2.2 ) Myocardial Infarction: The starting dosage depends upon tolerance of intravenous metoprolol, see full prescribing information.
( 2.3 ) 2.1 Hypertension Individualize the dosage of Lopressor tablets.
Lopressor tablets should be taken with or immediately following meals.
The usual initial dosage is 100 mg daily in single or divided doses.
Adjust dosage 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.
The effective dosage range of Lopressor tablets is 100 mg to 450 mg per day.
Dosages above 450 mg per day have not been studied.
While once-daily dosing can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period.
Larger or more frequent daily doses may be required.
Measure blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day.
2.2 Angina Pectoris The dosage of Lopressor tablets should be individualized.
Lopressor tablets should be taken with or immediately following meals.
The usual initial dosage is 100 mg daily, given in two divided doses.
Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate.
The effective dosage range of Lopressor tablets is 100 to 400 mg per day.
Dosages above 400 mg per day have not been studied.
If treatment is to be discontinued, reduce the dosage gradually over a period of 1 – 2 weeks [see Warnings and Precautions ( 5.1 ) ].
2.3 Myocardial Infarction See prescribing information of intravenous metoprolol for dosage instructions for intravenous therapy.
In patients who tolerate the full intravenous dose, initiate Lopressor tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose of metoprolol and continue for 48 hours.
In the case of intolerance, reduce dose to 25 mg and administer for 48 hours.
Titrate, based on tolerability, to a maintenance dosage of 100 mg twice daily.
Continue therapy for at least 3 months.
Although the efficacy of Lopressor beyond 3 months has not been conclusively established, data from studies with other beta-blockers suggest that treatment should be continued for 1 to 3 years.