What Is Metoprolol Succ Er 50 Mg Used for
What Is Metoprolol Succ Er 50 Mg Used for
What is Toprol Forty and how is it used?
Toprol XL is a prescription medicine used to care for the symptoms of chest pain (angina), high blood pressure (hypertension) and renal impairment. Toprol Twoscore may be used alone or with other medications.
Toprol XL belongs to a form of drugs called Thiazide Combos.
It is not known if Toprol 40 is rubber and effective in children younger than 18 years of historic period.
What are the possible side effects of Toprol XL?
Toprol Forty may cause serious side effects including:
- very deadening heartbeats,
- lightheadedness,
- shortness of breath,
- swelling,
- rapid weight gain, and
- common cold feeling in your hands and feet
Get medical help right away, if you accept whatsoever of the symptoms listed above.
The about common side furnishings of Toprol XL include:
- dizziness,
- tired feeling,
- depression,
- confusion,
- memory bug,
- nightmares,
- problem sleeping,
- diarrhea, and
- mild itching or rash
Tell the doctor if y'all accept any side effect that bothers you or that does not go away.
These are non all the possible side effects of Toprol XL. For more information, ask your doctor or pharmacist.
Call your physician for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
WARNING
ISCHEMIC HEART DISEASE
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 TOPROL-XL, particularly in patients with is chemical heart illness, the dos age should be gradually reduced over a period of 1 - 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, TOPROL-XL administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients confronting suspension or discontinuation of therapy without the dr.'s advice. Considering coronary avenue illness is common and may be unrecognized, it may be prudent non to discontinue TOPROL-XL therapy abruptly even in patients treated but for hypertension (see WARNINGS AND PRECAUTIONS ).
Clarification
TOPROL-Forty, metoprolol succinate, is a betaone-selective (cardioselective) adrenoceptor blocking amanuensis, for oral administration, bachelor equally extended-release tablets. TOPROL-XL has been formulated to provide a controlled and predictable release of metoprolol for one time-daily administration. The tablets comprise a multiple unit of measurement system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a split up drug commitment unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)i- (isopropylamino)-iii-[p-(two-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
Metoprolol succinate is a white crystalline powder with a molecular weight of 652.viii. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, methane series.
3 pharmacies near 11430 have coupons for FIRST-Metoprolol (Brand Names:Toprol XL for 50MG)
INDICATIONS
Hypertension
TOPROL-Twoscore is indicated for the handling of hypertension, to lower blood pressure. Lowering blood pressure lowers the hazard 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 broad diverseness of pharmacologic classes including metoprolol.
Control of high blood force per unit area should exist part of comprehensive cardiovascular risk management, including, every bit appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients volition require more 1 drug to achieve blood pressure goals. For specific communication on goals and management, see published guidelines, such as those of the National Loftier Blood Pressure Education Program’southward Articulation 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 bloodshed, and it tin can be concluded that information technology is claret pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and virtually 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 hazard, and the absolute risk increase per mmHg is greater at higher claret pressures, so that even modest reductions of astringent hypertension can provide substantial benefit. Relative risk reduction from blood force per unit area reduction is similar across populations with varying absolute risk, so the absolute do good is greater in patients who are at higher hazard independent of their hypertension (for instance, patients with diabetes or hyperlipidemia), and such patients would be expected to do good from more ambitious treatment to a lower blood pressure goal.
Some antihypertensive drugs take smaller blood pressure furnishings (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney affliction). These considerations may guide pick of therapy.
TOPROL-Xl may be administered with other antihypertensive agents.
Angina Pectoris
TOPROL-40 is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve practice tolerance.
Center Failure
TOPROL-Twoscore is indicated to reduce the risk of cardiovascular mortality and heart-failure hospitalization in patients with heart failure.
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QUESTION
Salt and sodium are the aforementioned. Run into AnswerDOSAGE AND Assistants
Hypertension
Adults
The usual initial dosage is 25 to 100 mg daily in a single dose. Adjust dosage at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In full general, the maximum result of any given dosage level volition exist credible after 1 calendar week of therapy. Dosages higher up 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ half dozen Years Of Historic period
The recommended starting dose of TOPROL-XL is i mg/kg once daily, merely the maximum initial dose should non exceed 50 mg once daily. Adjust dosage according to blood pressure response. Doses above 2 mg/kg (or in excess of 200 mg) in one case daily have not been studied in pediatric patients [see Use In Specific Populations and CLINICAL PHARMACOLOGY].
TOPROL-XL has not been studied in pediatric patients < 6 years of age [see Use In Specific Populations].
Angina Pectoris
Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a unmarried dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per solar day have not been studied. If handling is to be discontinued, reduce the dosage gradually over a period of 1 - ii weeks [see WARNINGS AND PRECAUTIONS].
Heart Failure
Dosage must be individualized and closely monitored during upward-titration. Prior to initiation of TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended starting dose of TOPROL-XL is 25 mg one time daily for two weeks in patients with NYHA Course 2 heart failure and 12.v mg one time daily in patients with more than severe heart failure. Double the dose every 2 weeks to the highest dosage level tolerated past the patient or upward to 200 mg of TOPROL-XL. Initial difficulty with titration should not preclude later attempts to introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of TOPROL-40 or temporarily discontinuing it. The dose of TOPROL-Twoscore should non be increased until symptoms of worsening heart failure have been stabilized.
Administration
TOPROL-Twoscore tablets are scored and tin be divided; nonetheless, practice non crush or chew the whole or half tablet.
HOW SUPPLIED
Dosage Forms And Strengths
25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with "A/β".
50 mg tablets: White, round, arched, film-coated scored tablet engraved with "A/mo".
100 mg tablets: White, round, arched, picture-coated scored tablet engraved with "A/ms".
200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with "A/my".
Storage And Handling
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, arched, film-coated, and scored.
Tablet | Shape | Engraving | Bottle of 100 NDC 70347- | Bottle of chiliad NDC 70347- |
25 mg | Oval | A/ P | 025-02 | 025-03 |
50 mg | Round | A/ mo | 050-02 | 050-03 |
100 mg | Circular | A/ ms | 100-02 | 100-03 |
200 mg | Oval | A/ my | 200-02 | 200-03 |
Shop at 25°C (77°F). Excursions permitted to 15-thirty°C (59-86°F). (See USP Controlled Room Temperature.)
Manufactured for: Aralez Pharmaceuticals US Inc., 300 Interpace Parkway, Morris Corporate Center 1, Building C3, Parsippany, NJ 07054. Revised: Jan 2022
SIDE Furnishings
The following adverse reactions are described elsewhere in labeling:
- Worsening angina or myocardial infarction [see WARNINGS AND PRECAUTIONS]
- Worsening heart failure [run across WARNINGS AND PRECAUTIONS].
- Worsening AV block [see CONTRAINDICATIONS].
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot exist direct compared to rates in the clinical trials of another drug and may not reverberate the rates observed in do. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Hypertension And Angina
Most agin reactions accept been mild and transient. The near common (>two%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.
Heart Failure
In the MERIT-HF report comparing TOPROL-Xl in daily doses up to 200 mg (mean dose 159 mg oncedaily; north=1990) to placebo (n=2001), 10.3% of TOPROL-XL patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The tabular array below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the TOPROL-XL group and greater than placebo by more than than 0.5%, regardless of the assessment of causality.
Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥1% in the TOPROL-XL Group and Greater Than Placebo by More Than 0.5%
TOPROL-XL n=1990 % of patients | Placebo n=2001 % of patients | |
Dizziness/vertigo | 1.8 | i.0 |
Bradycardia | 1.5 | 0.4 |
Postal service-operative Adverse Events
In a randomized, double-bullheaded, placebo-controlled trial of 8351 patients with or at run a risk for atherosclerotic disease undergoing not-vascular surgery and who were not taking beta-blocker therapy, TOPROL-40 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. TOPROL-XL use was associated with a college incidence of bradycardia (half-dozen.6% vs. two.4%; HR, 2.74; 95% CI ii.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and decease (3.1% vs. 2.three%; HR i.33; 95% CI ane.03, 1.74) compared to placebo.
Post-Marketing Experience
The following adverse reactions have been identified during post-approval utilise of TOPROL-Xl or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or constitute a causal human relationship to drug exposure.
Cardiovascular: Cold extremities, arterial insufficiency (commonly of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.
Respiratory: Wheezing (bronchospasm), dyspnea.
Central Nervous Organisation: Confusion, brusk-term memory loss, headache, somnolence, nightmares, insomnia, feet/nervousness, hallucinations, paresthesia.
Gastrointestinal: Nausea, dry out mouth, constipation, flatulence, heartburn, hepatitis, airsickness.
Hypersensitive Reactions: Pruritus.
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosensitivity, gustatory modality disturbance.
Potential Adverse Reactions
In add-on, there are adverse reactions non listed above that have been reported with other beta-adrenergic blocking agents and should exist considered potential adverse reactions to TOPROL-XL.
Primal Nervous Organization: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized past disorientation for time and identify, short-term memory loss, emotional lability, clouded sensorium, and decreased functioning on neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm, respiratory distress.
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SLIDESHOW
How to Lower Blood Pressure level: Exercise Tips Come across SlideshowDRUG INTERACTIONS
Catecholamine Depleting Drugs
Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may accept an condiment effect when given with beta-blocking agents. Discover patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
CYP2D6 Inhibitors
Drugs that are stiff inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no data about moderate or weak inhibitors, these also are likely to increase metoprolol concentration. Increases in plasma concentration subtract the cardioselectivity of metoprolol [see CLINICAL PHARMACOLOGY]. Monitor patients closely, when the combination cannot be avoided.
Digitalis, Clonidine, And Calcium Channel Blockers
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease center rate. Concomitant utilize with beta blockers tin can increment 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 tin follow the withdrawal of clonidine. If replacing clonidine past beta-blocker therapy, filibuster the introduction of beta-blockers for several days after clonidine administration has stopped.
WARNINGS
Included as function of the PRECAUTIONS department.
PRECAUTIONS
Precipitous Cessation Of Therapy
Post-obit 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 TOPROL-XL, peculiarly in patients with ischemic heart disease, gradually reduce the dosage over a menstruum of 1 to ii weeks and monitor the patient. If angina markedly worsens or astute coronary ischemia develops, promptly reinstate TOPROL-Xl, and accept measures advisable for the management of unstable angina. Warn patients not to interrupt therapy without their physician’due south communication. Because coronary avenue affliction is common and may be unrecognized, avoid abruptly discontinuing TOPROL-XL in patients treated only for hypertension.
Centre Failure
Worsening cardiac failure may occur during upwardly-titration of TOPROL-XL. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of TOPROL-Forty [run across DOSAGE AND Assistants]. It may be necessary to lower the dose of TOPROL-Twoscore or temporarily discontinue it. Such episodes exercise non prevent subsequent successful titration of TOPROL-XL.
Bronchospastic Disease
Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta1 cardioselectivity, still, TOPROL-XL may exist used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, utilize the lowest possible dose of TOPROL-Xl. Bronchodilators, including beta2-agonists, should be readily bachelor or administered concomitantly [see DOSAGE AND ADMINISTRATION].
Bradycardia
Bradycardia, including sinus suspension, heart cake, and cardiac abort accept occurred with the utilise of TOPROL-Twoscore. Patients with kickoff-caste atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff- Parkinson-White) or on concomitant drugs that cause bradycardia [see DRUG INTERACTIONS], may exist at increased gamble. Monitor middle charge per unit in patients receiving TOPROL-Twoscore. If severe bradycardia develops, reduce or cease TOPROLXL.
Pheochromocytoma
If TOPROL-XL is used in the setting of pheochromocytoma, it should exist given in combination with an blastoff blocker, and but after the blastoff blocker has been initiated. Assistants of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increment in claret pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Major Surgery
Avert initiation of a high-dose regimen of extended-release metoprolol in patients undergoing not-cardiac surgery, since such apply in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta-blocking therapy should not exist routinely withdrawn prior to major surgery, however, the dumb ability of the centre to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Mask Symptoms Of Hypoglycemia
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not exist significantly affected.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Sharp withdrawal of beta-blockade may precipitate a thyroid storm.
Peripheral Vascular Affliction
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may exist more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals accept been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In two-year studies in rats at three oral dosage levels of up to 800 mg/kg/mean solar day (41 times, on a mg/m² basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring beneficial or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of by and large balmy focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-calendar month written report in Swiss albino mice at three oral dosage levels of upwards to 750 mg/kg/solar day (xviii times, on a mg/m² basis, the daily dose of 200 mg for a lx-kg patient), benign lung tumors (pocket-size adenomas) occurred more oft in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (beneficial plus malignant) lung tumors, nor in the overall incidence of tumors or cancerous tumors. This 21-calendar month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex activity for whatever type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly exam in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity examination) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a report performed in rats at doses upwards to 22 times, on a mg/m² ground, the daily dose of 200 mg in a sixty-kg patient.
Use In Specific Populations
Pregnancy
Risk Summary
Untreated hypertension and middle failure during pregnancy can pb to adverse outcomes for the female parent and the fetus (see Clinical Considerations). Available data from published observational studies take not demonstrated a drug-associated risk of major nascency defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm nativity, and perinatal mortality with maternal use of beta blockers, including metoprolol, during pregnancy (encounter Information). In fauna reproduction studies, metoprolol has been shown to increment post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, approximately 24 times the daily dose of 200 mg in a threescore-kg patient on a mg/m² basis.
The estimated groundwork gamble of major nascence defects and miscarriage for the indicated population is unknown. All pregnancies have a groundwork hazard of nascency defect, loss, or other adverse outcomes. In the U.Southward. general population, the estimated background risk of major nativity defects and miscarriage in clinically recognized pregnancies is two to 4% and 15 to xx%, 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 take a chance for intrauterine growth restriction and intrauterine death. Significant women with hypertension should be advisedly monitored and managed accordingly.
Stroke book and center rate increase during pregnancy, increasing cardiac output, especially during the first trimester. At that place is a risk for preterm nativity with significant women with chronic middle failure in tertiary trimester of pregnancy.
Fetal/Neonatal Adverse Reactions
Metoprolol crosses the placenta. Neonates built-in to mothers who are receiving metoprolol during pregnancy, may exist at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Detect neonates and manage appropriately.
Data
Human Data
Information from published observational studies did not demonstrate an association of major congenital malformations and employ of metoprolol in pregnancy. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm nativity and perinatal mortality with maternal use of metoprolol during pregnancy; withal, these studies accept methodological limitations hindering estimation. Methodological limitations include retrospective blueprint, concomitant use of other medications, and other unadjusted confounders that may business relationship for the written report findings including the underlying illness in the mother. These observational studies cannot definitely establish or exclude whatever drug-associated run a risk during pregnancy.
Animate being Data
Metoprolol has been shown to increase mail service-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.due east., 24 times, on a mg/m² basis, the daily dose of 200 mg in a sixty-kg patient.
No fetal abnormalities were observed when meaning rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e., x times, the daily dose of 200 mg in a lx-kg patient.
Lactation
Risk Summary
Limited available data from published literature written report that metoprolol is present in human milk. The estimated daily babe dose of metoprolol received from breastmilk ranges from 0.05 mg to less than 1 mg. The estimated relative baby dosage was 0.5% to 2% of the mother'due south weight-adjusted dosage (see Information). No adverse reactions of metoprolol on the breastfed babe have been identified. There is no information regarding the furnishings of metoprolol on milk production.
Clinical Consideration
Monitoring For Agin Reactions
Monitor the breastfed baby for bradycardia and other symptoms of beta blockade such every bit listlessness (hypoglycemia).
Data
Based on published instance reports, the estimated infant daily dose of metoprolol received from breast milk range from 0.05 mg to less than ane mg. The estimated relative infant dosage was 0.5% to 2% of the mother’s weightadjusted dosage.
In ii women who were taking unspecified amount of metoprolol, milk samples were taken after i dose of metoprolol. The estimated amount of metoprolol and alpha-hydroxy metoprolol in chest milk is reported to exist less than 2% of the female parent'due south weight-adjusted dosage.
In a modest study, breast milk was collected every two to iii hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. The average corporeality of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.vii). The boilerplate relative infant dosage was 0.5% of the mother'southward weight-adjusted dosage.
Females And Males Of Reproductive Potential
Risk Summary
Based on the published literature, beta blockers (including metoprolol) may crusade erectile dysfunction and inhibit sperm movement.
No evidence of impaired fertility due to metoprolol was observed in rats [run into Nonclinical Toxicology].
Pediatric Employ
Ane hundred twoscore-four hypertensive pediatric patients aged half dozen to 16 years were randomized to placebo or to 1 of iii dose levels of TOPROL-Xl (0.2, 1or two mg/kg one time daily) and followed for four weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including:
- Dose-response for reduction in DBP,
- 1 mg/kg vs. placebo for change in SBP, and
- 2 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from iii to half-dozen mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see DOSAGE AND Administration].
No clinically relevant differences in the adverse effect contour were observed for pediatric patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of TOPROL-XL have non been established in patients < half dozen years of age.
Geriatric Utilise
Clinical studies of TOPROL-XL 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 betwixt elderly and younger patients.
Of the 1,990 patients with heart failure randomized to TOPROL-XL in the MERIT-HF trial, l% (990) were 65 years of age and older and 12% (238) were 75 years of historic period and older. There were no notable differences in efficacy or the rate of adverse reactions betwixt older and younger patients.
In full general, utilise a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant illness or other drug therapy.
Hepatic Impairment
No studies have been performed with TOPROL-XL in patients with hepatic harm. Considering TOPROL-XL is metabolized by the liver, metoprolol blood levels are probable to increase substantially with poor hepatic office. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increment doses gradually in patients with impaired hepatic function.
Renal Impairment
The systemic availability and one-half-life of metoprolol in patients with renal failure practise not differ to a clinically significant caste from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure [run across CLINICAL PHARMACOLOGY].
Overdosage & Contraindications
OVERDOSE
Signs And Symptoms
Overdosage of TOPROL-40 may atomic number 82 to severe bradycardia, hypotension, and cardiogenic stupor. Clinical presentation can as well include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.
Handling
Consider treating the patient with intensive intendance. 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 [run across CLINICAL PHARMACOLOGY].
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 every bit dopamine or norepinephrine.
Heart Failure And Shock
May be treated when appropriate with suitable book 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
Tin can normally be reversed past bronchodilators.
CONTRAINDICATIONS
TOPROL-Twoscore is contraindicated in severe bradycardia, second or third degree centre cake, cardiogenic shock, decompensated center failure, ill sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.
CLINICAL PHARMACOLOGY
Mechanism Of Action
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is non absolute, however, and at college plasma concentrations, metoprolol likewise inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable just at plasma concentrations much greater than required for beta-blockade. Animal and human experiments point that metoprolol slows the sinus rate and decreases AV nodal conduction.
The relative beta1-selectivity of metoprolol has been confirmed by the post-obit: (ane) In normal subjects, metoprolol is unable to opposite the beta2-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 FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
Hypertension
The machinery of the antihypertensive furnishings 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; (two) a cardinal effect leading to reduced sympathetic outflow to the periphery; and (iii) suppression of renin activity.
Angina Pectoris
Past blocking catecholamine-induced increases in centre rate, in velocity and extent of myocardial contraction, and in blood pressure level, metoprolol reduces the oxygen requirements of the heart at whatever given level of effort, thus making it useful in the long-term direction of angina pectoris.
Heart Failure
The precise machinery for the beneficial effects of beta-blockers in heart failure has not been elucidated.
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 force per unit area upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (four) reduction of reflex orthostatic tachycardia.
The relationship between plasma metoprolol levels and reduction in practise heart rate is independent of the pharmaceutical formulation. Beta1-blocking effects in the range of 30-80% of the maximal upshot (approximately eight to 23% reduction in practise heart rate) correspond to metoprolol plasma concentrations from xxx to 540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.
In five controlled studies in normal healthy subjects, extended-release metoprolol succinate administered once a mean solar day, and immediate-release metoprolol administered once to 4 times a day, provided comparable total beta1-occludent over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100 to 400 mg. In another controlled study, 50 mg once daily for each product, extended-release metoprolol succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release metoprolol. For extended-release metoprolol succinate, the pct reduction in practise center rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from fifty to 300 mg daily.
A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., and 100 mg and 200 mg extended-release metoprolol succinate once daily. Extended-release metoprolol succinate 200 mg once daily produced a larger result on suppression of do-induced and Holter-monitored heart rate over 24 hours compared to fifty mg t.i.d. of firsthand-release metoprolol.
In other studies, treatment with metoprolol succinate produced an improvement in left ventricular ejection fraction. Metoprolol succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes subsequently half dozen months of handling.
Although beta-adrenergic receptor occludent is useful in the handling of angina, hypertension, and heart failure at that place 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 forbid the necessary facilitating effect of sympathetic action on conduction. Beta2-adrenergic occludent results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activeness in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
Pharmacokinetics
Absorption
The peak plasma levels following once-daily administration of TOPROL-Forty average one-fourth to half the pinnacle plasma levels obtained following a respective dose of conventional metoprolol, administered once daily or in divided doses. At steady country the average bioavailability of metoprolol following administration of TOPROL-40, across the dosage range of 50 to 400 mg once daily, was 77% relative to the respective single or divided doses of conventional metoprolol.
The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is non significantly afflicted by food following TOPROL-Xl administration.
The peak plasma levels following oral administration of conventional metoprolol tablets, however, approximate fifty% of levels following intravenous assistants, indicating about fifty% starting time-pass metabolism.
Distribution
Metoprolol crosses the claret-encephalon barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Simply a small fraction of the drug (near 12%) is bound to human serum albumin.
Metabolism
Metoprolol is a racemic mixture of R- and S- enantiomers and is primarily metabolized by CYP2D6. When administered orally, information technology exhibits stereoselective metabolism that is dependent on oxidation phenotype.
Emptying
Elimination is mainly by biotransformation in the liver, and the plasma one-half-life ranges from approximately 3 to vii hours. 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 beta-blocking activity.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%.
Specific Populations
Patients With Renal Harm
The systemic availability and half-life of metoprolol in patients with renal failure practice not differ to a clinically significant degree from those in normal subjects.
Pediatric Patients
The pharmacokinetic profile of TOPROL-Xl was studied in 120 pediatric hypertensive patients (six-17 years of age) receiving doses ranging from 12.v to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Metoprolol pharmacokinetics have non been investigated in patients < 6 years of age.
Body Weight, Age, And Race
Metoprolol apparent oral clearance (CL/F) increased linearly with torso weight. Age, gender, and race had no significant effects on metoprolol pharmacokinetics.
Drug Interactions
CYP2D6
Metoprolol is metabolized predominantly past CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a stiff CYP2D6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediaterelease metoprolol l mg t.i.d. resulted in steady-state concentration of metoprolol two- to 5-fold what is seen with metoprolol lonely. All-encompassing metabolizers who concomitantly employ CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol claret levels, decreasing metoprolol'due south cardioselectivity [run across DRUG INTERACTIONS].
Pharmacogenomics
CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about ii% of nigh other populations. CYP2D6 tin exist inhibited past several drugs. Poor metabolizers of CYP2D6 will accept increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity.
Clinical Studies
Hypertension
In a double-blind written report, 1092 patients with balmy-to-moderate hypertension were randomized to once daily TOPROL-40 (25, 100, or 400 mg), PLENDIL® (felodipine extended-release tablets), the combination, or placebo. After 9 weeks, TOPROL-XL lonely decreased sitting blood pressure past 6-8/iv-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of TOPROL-Forty with PLENDIL has greater furnishings on claret pressure.
In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive amanuensis when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. TOPROL-40, in dosages of 100 to 400 mg once daily, produces similar β1-occludent equally conventional metoprolol tablets administered two to iv times daily. In addition, TOPROL-Xl administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Considering of variable plasma levels attained with a given dose and lack of a consistent human relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
Angina Pectoris
In controlled clinical trials, an immediate-release formulation of metoprolol has been shown to be an effective antianginal amanuensis, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg one time daily, has been shown to possess betablockade similar to conventional metoprolol tablets administered two to four times daily.
Heart Failure
MERIT-HF was a randomized double-bullheaded, placebo-controlled study of TOPROL-Xl in which 3991 patients with ejection fraction ≤0.40 and NYHA Class Ii-IV eye failure attributable to ischemia, hypertension, or cardiomyopathy were randomized i:ane to TOPROL XL or placebo. The protocol excluded patients with contraindications to betablocker use, those expected to undergo center surgery, and those inside 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (ane) all-cause mortality plus all-cause hospitalization (time to kickoff result) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Form 3; 65% of patients had heart failure attributed to ischemic middle illness; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean elapsing of follow-upwards was one yr. At the end of the report, the mean daily dose of TOPROL-XL was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The take chances of all-cause mortality plus all-cause hospitalization was reduced past 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional course.
The tabular array below shows the principal results for the overall study population. The effigy below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-U.s.a. populations (the latter of which was not prespecified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups. Nonetheless, subgroup analyses can be difficult to translate, and information technology is not known whether these represent true differences or adventure effects.
Clinical Endpoints in the MERIT-HF Study
Clinical Endpoint | Number of Patients | Relative Risk (95% Cl) | Risk Reduction With TOPROL-Forty | Nominal P-value | |
Placebo n=2001 | TOPROL- XL due north=1990 | ||||
All-crusade mortality plus allcaused hospitalization1 | 767 | 641 | 0.81 (0.73- 0.xc) | 19% | 0.00012 |
All-crusade mortality | 217 | 145 | 0.66 (0.53- 0.81) | 34% | 0.00009 |
All-cause mortality plus heart failure hospitalization1 | 439 | 311 | 0.69 (0.60- 0.80) | 31% | 0.0000008 |
Cardiovascular bloodshed | 203 | 128 | 0.62 (0.50- 0.78) | 38% | 0.000022 |
Sudden death | 132 | 79 | 0.59 (0.45- 0.78) | 41% | 0.0002 |
Death due to worsening heart failure | 58 | 30 | 0.51 (0.33- 0.79) | 49% | 0.0023 |
Hospitalizations due to worsening centre failure2 | 451 | 317 | Northward/A | N/A | 0.0000076 |
Cardiovascular hospitalization2 | 773 | 649 | N/A | North/A | 0.00028 |
1 Time to first event 2 Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative take chances and gamble reduction are not applicable. |
Results for Subgroups in MERIT - HF
PATIENT INFORMATION
Propose patients to take TOPROL-Forty regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should have only the side by side scheduled dose (without doubling it). Patients should non interrupt or discontinue TOPROL-XL without consulting the md.
Advise patients (ane) to avert operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with TOPROL-40 has been adamant; (ii) to contact the medico if whatsoever difficulty in animate occurs; (iii) to inform the doc or dentist before whatever blazon of surgery that he or she is taking TOPROL-XL.
Heart failure patients should exist advised to consult their physician if they experience signs or symptoms of worsening eye failure such as weight gain or increasing shortness of breath.
Study Bug to the Food and Drug Administration
You are encouraged to written report negative side furnishings of prescription drugs to the FDA. Visit the FDA MedWatch website or call i-800-FDA-1088.
What Is Metoprolol Succ Er 50 Mg Used for
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