Metoprolol succinate tablet, extended release
Warning: ischemic heart disease:
WARNING: ISCHEMIC HEART DISEASE
See full prescribing information for complete boxed warning.
Following abrupt cessation of therapy with beta-blocking agents, exacerbations of angina pectoris and myocardial infarction have occurred. Warn patients against interruption or discontinuation of therapy without the physician's advice. ( 5.1)
Spl unclassified section
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 metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, the dosage 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, metoprolol succinate extended-release tablet administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients 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 succinate extended-release tablet therapy abruptly even in patients treated only for hypertension ( 5.1).
1 indications and usage
Metoprolol succinate, is a beta 1-selective adrenoceptor blocking agent.
Metoprolol succinate extended-release tablets, USP are 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)
- Heart Failure - for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. ( 1.3)
2 dosage and administration
- Administer once daily. Dosing of metoprolol succinate extended-release tablets, USP should be individualized. ( 2)
- Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled every two weeks to the highest dose tolerated or up to 200 mg. ( 2.3)
- Hypertension: Usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied. ( 2.1)
- Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is an unacceptable bradycardia. Dosages above 400 mg per day have not been studied. ( 2.2)
- Switching from immediate-release metoprolol to metoprolol succinate extended-release tablets: use the same total daily dose of metoprolol succinate extended-release tablets. ( 2)
Spl unclassified section
Metoprolol succinate extended-release tablets are an extended-release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to metoprolol succinate extended-release tablets, use the same total daily dose of metoprolol succinate extended-release tablets. Individualize the dosage of metoprolol succinate extended- release tablets. Titration may be needed in some patients.
Metoprolol succinate extended-release tablets are scored on both sides and can be divided; however, do not crush or chew the whole or half tablet.
3 dosage forms and strengths
Spl unclassified section
25 mg tablets white, oval, biconvex, scored on both sides, film-coated tablet engraved with "N / 25".
50 mg tablets white, round, biconvex, scored on both sides, film-coated tablet engraved with "N / 50".
100 mg tablets white, round, biconvex, scored on both sides, film-coated tablet engraved with "N / 100".
200 mg tablets white, oval, biconvex, scored on both sides, film-coated tablet engraved with "N / 200".
Spl unclassified section
Metoprolol succinate extended-release tablets are contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.
5 warnings and precautions
- Heart Failure: Worsening cardiac failure may occur. ( 5.2)
- Bronchospastic Disease: Avoid beta blockers. ( 5.3)
- Pheochromocytoma: If required, first initiate therapy with an alpha blocker. ( 5.4)
- Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery because it has been associated with bradycardia, hypotension, stroke and death. Do not routinely withdraw chronic beta blocker therapy prior to surgery. ( 5.5, 6.1)
- Diabetes and Hypoglycemia: May mask tachycardia occurring with hypoglycemia. ( 5.6)
- Patients with Hepatic Impairment: ( 5.7)
- Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. ( 5.8)
- Anaphylactic Reactions: Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. ( 5.9)
- Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. ( 5.10)
- Calcium Channel Blockers: Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly. ( 5.11)
6 adverse reactions
7 drug interactions
- Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. ( 7.1)
- CYP2D6 Inhibitors are likely to increase metoprolol concentration. ( 7.2)
- Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. ( 7.3)
- Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. ( 7.3)
8 use in specific populations
- Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use this drug during pregnancy only if clearly needed. ( 8.1)
- Nursing Mothers: Consider possible infant exposure. ( 8.3)
- Pediatrics: Safety and effectiveness have not been established in patients < 6 years of age. ( 8.4)
- Geriatrics: No notable difference in efficacy or safety vs. younger patients. ( 8.5)
- Hepatic Impairment: Consider initiating metoprolol succinate extended-release tablet therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. ( 8.6)
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m 2basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
8.3 nursing mothers
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when metoprolol succinate extended-release tablets are administered to a nursing woman.
8.4 pediatric use
One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metoprolol succinate extended-release tablets. (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 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 3 to 6 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 (2.1)].
No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients < 6 years of age.
8.5 geriatric use
Clinical studies of metoprolol succinate extended-release tablets in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.
Of the 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older 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.
Signs and Symptoms - Overdosage of metoprolol succinate extended-release tablets may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.
Treatment Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. 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.
There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound.
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 1receptor agonistic drugs added in presence of vasodilation.
Bronchospasm: Can usually be reversed by bronchodilators.
Metoprolol succinate, is a beta 1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended-release tablets. Metoprolol succinate extended-release tablets, USP have been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery 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 ()1- (isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
Metoprolol succinate, USP is a white crystalline powder with a molecular weight of 652.8. 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: sugar spheres, povidone, ethyl cellulose, polyethylene glycol, hydroxypropyl cellulose, triethyl citrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, polydextrose, hypromellose, and triacetin.
12 clinical pharmacology
12.1 mechanism of action
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.
Heart Failure:The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
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 1and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta 1-receptor blocking doses.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an E maxmodel, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta 1-blockade. Beta 1-blocking effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta 1-selectivity of metoprolol diminishes and blockade of beta 2-adrenoceptors increases at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta 2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In other studies, treatment with metoprolol succinate extended-release tablets produced an improvement in left ventricular ejection fraction. Metoprolol succinate extended-release tablets was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
Adults:In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 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%. 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 metoprolol succinate dosage is usually needed in patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2)].
In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol succinate extended-release tablets are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of metoprolol succinate extended-release tablets average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of metoprolol succinate extended-release tablets, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, 1-blockade is comparable and dose-related [see Clinical Pharmacology (12)]. The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol succinate extended-release tablets administration.
Pediatrics:The pharmacokinetic profile of metoprolol succinate extended-release tablets was studied in 120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.
13 nonclinical toxicology
14 clinical studies
In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate extended-release tablets and immediate-release metoprolol were compared in terms of the extent and duration of beta 1- blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate-release metoprolol per day. In these studies, metoprolol succinate extended-release tablets was administered once a day and immediate-release metoprolol was administered once to four times a day. A sixth controlled study compared the beta 1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta 1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate extended-release tablets administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta 1-blockade over 24 hours (area under the beta 1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, metoprolol succinate extended-release tablets produced significantly higher total beta 1-blockade over 24 hours than immediate-release metoprolol. For metoprolol succinate extended-release tablets, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta 1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (i.e., at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate extended-release tablets once a day, respectively. In contrast to metoprolol succinate extended-release tablets, immediate-release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate extended-release tablets over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta 1-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate extended-release tablets once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate extended-release tablets. A 200 mg dose of metoprolol succinate extended-release tablets produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate extended-release tablets (25, 100, or 400 mg), felodipine extended-release tablets, the combination, or placebo. After 9 weeks, metoprolol succinate extended-release tablets alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate extended-release tablets with felodipine extended-release tablets has greater effects on blood pressure.
In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, produces similar 1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release tablets 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. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008; 371:1839-47.
16 how supplied/storage and handling
Tablets containing metoprolol succinat, USP equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored on both sides.
NDC 68071-4363-3 BOTTLES OF 30
NDC 68071-4363-6 BOTTLES OF 60
NDC 68071-4363-9 BOTTLES OF 90
Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]
17 patient counseling information
Advise patients to take metoprolol succinate extended-release tablets 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 metoprolol succinate extended-release tablets 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 metoprolol succinate extended-release tablets 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 metoprolol succinate extended-release tablets.
Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
Manufactured for: Ingenus Pharmaceuticals LLC
Orlando, FL 32839-6408
Customer toll-free number: 1-877-748-1970
Manufactured by: Novast Laboratories Ltd.
Nantong, China 226009
Ingredients and appearance - Product information
Metoprolol succinate tablet, extended release- Metoprolol succinate
|Product Type||HUMAN PRESCRIPTION DRUG LABEL||Item Code (Source)||NDC: 68071-4363|
|Route of Administration||Oral|
|Metoprolol succinate ( UNII: TH25PD4CCB)( Metoprolol - UNII: GEB06NHM23 )||50 mgin 1|
|Povidone, unspecified||( UNII: FZ989GH94E)|
|Ethylcelluloses||( UNII: 7Z8S9VYZ4B)|
|Polyethylene glycol, unspecified||( UNII: 3WJQ0SDW1A)|
|Hydroxypropyl cellulose||( UNII: RFW2ET671P)|
|Triethyl citrate||( UNII: 8Z96QXD6UM)|
|Magnesium stearate||( UNII: 70097M6I30)|
|Cellulose, microcrystalline||( UNII: OP1R32D61U)|
|Titanium dioxide||( UNII: 15FIX9V2JP)|
|Polydextrose||( UNII: VH2XOU12IE)|
|Hypromelloses||( UNII: 3NXW29V3WO)|
|Triacetin||( UNII: XHX3C3X673)|
|#||Item Code||Package Description||Marketing Start Date|
|1||NDC: 68071-4363-3||30 in 1 BOTTLE||2018/03/30|
|2||NDC: 68071-4363-6||60 in 1 BOTTLE||2018/03/30|
|3||NDC: 68071-4363-9||90 in 1 BOTTLE||2018/03/30|
|Marketing Category||Application Number or Monograph Citation||Territorial Authority||Marketing Start Date|
Labeler - NuCare Pharmaceuticals,Inc.( 010632300)
|NuCare Pharmaceuticals,Inc.||010632300||repack( 68071-4363)|