Metoprolol Succinate Extended Release Tablets
TABLE OF CONTENTS
Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent, available as extended release tablets for once-daily administration.
Its chemical name is (+) 1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
Metoprolol succinate extended-release (ER) has 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.
Metoprolol succinate 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: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin.
|2. INDICATIONS AND USAGE|
Metoprolol succinate is indicated for the treatment of hypertension, 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 (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Metoprolol succinate may be administered with other antihypertensive agents.
2.2 Angina Pectoris
Metoprolol succinate is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.
2.3 Heart Failure
Metoprolol succinate is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, metoprolol succinate decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
|3. DOSAGE AND ADMINISTRATION|
Metoprolol succinate ER is an extended release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate release metoprolol to metoprolol succinate ER, use the same total daily dose of metoprolol succinate ER. Individualize the dosage of metoprolol succinate ER. Titration may be needed in some patients.
Metoprolol succinate ER tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.
Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased 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. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose of metoprolol succinate ER is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)].
Metoprolol succinate ER is not recommended in pediatric patients < 6 years of age [see Use in Specific Populations].
3.2 Angina Pectoris
Individualize the dosage of metoprolol succinate ER. The usual initial dosage is 100 mg daily, given in a single 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 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].
3.3 Heart Failure
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate ER, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate ER is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of TOPROL- XL. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate ER. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate ER. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate ER or temporarily discontinuing it. The dose of metoprolol succinate ER should not be increased until symptoms of worsening heart failure have been stabilized.
Metoprolol succinate is 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. MECHANISM OF ACTION|
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
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/m2 basis, 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.
6.2 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. Caution should be exercised when metoprolol succinate is administered to a nursing woman.
6.3 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 (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,
• 1.0 mg/kg vs. placebo for change in SBP, and
• 2.0 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].
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 have not been established in patients < 6 years of age.
6.4 Geriatric Use
Clinical studies of metoprolol succinate 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 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.
6.5 Hepatic Impairment
No studies have been performed with metoprolol succinate in patients with hepatic impairment. Because metoprolol succinate is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.
6.6 Renal Impairment
The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure.
|7. WARNINGS AND PRECAUTIONS|
7.1 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 metoprolol succinate ER, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate ER, 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 metoprolol succinate ER in patients treated only for hypertension.
7.2 Heart Failure
Worsening cardiac failure may occur during up-titration of metoprolol succinate ER. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of TOPROLXL [see Dosage and Administration]. It may be necessary to lower the dose of TOPROLXL or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate ER.
7.3 Bronchospastic Disease
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, metoprolol succinate ER may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol succinate ER. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly, [see Dosage and Administration].
If metoprolol succinate ER 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.
7.5 Major Surgery
Avoid initiation of a high-dose regimen of extended release metoprolol 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.
7.6 Diabetes and Hypoglycemia
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
7.7 Hepatic Impairment
Consider initiating metoprolol succinate ER therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
7.9 Anaphylactic Reaction
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.
7.10 Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
7.11 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.
|8. ADVERSE REACTIONS|
The following adverse reactions are described elsewhere in labeling:
• Worsening angina or myocardial infarction. [see Warnings and Precautions]
• Worsening heart failure. [see Warnings and Precautions]
• Worsening AV block. [see Contraindications]
8.1 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. 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.
Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.
Heart Failure: In the MERIT-HF study comparing metoprolol succinate ER in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate ER patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the metoprolol succinate ER group and greater than placebo by more than 0.5%, regardless of the assessment of causality.
Table 1. Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1 % in the Metoprolol Succinate ER Group and Greater Than Placebo by More Than 0.5 %
Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, metoprolol succinate ER 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate ER use was associated with a higher incidence of bradycardia (6.6% vs. 2.4% ; HR 2.74; 95% CI 2.19,3.43), 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 death (3.1% vs 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.
8.2 Laboratory Test Findings
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
Overdosage of metoprolol succinate may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness/coma, nausea, vomiting, and cyanosis.
In general, patients with acute or recent myocardial infarction or congestive heart failure may be more hemodynamically unstable than other patients and should be treated accordingly. On the basis of the pharmacologic actions of metoprolol, the following general measures should be employed:
Elimination of the Drug: Gastric lavage should be performed.
Bradycardia: Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.
Hypotension: A vasopressor should be administered, eg, levarterenol or dopamine.
Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be administered.
Cardiac Failure: A digitalis glycoside and diuretics should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon may be considered.
|10. DRUG INTERACTIONS|
10.1 Catecholamine Depleting Drugs
Catecholamine depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
10.2 CYP2D6 Inhibitors
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg 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 three times daily with immediate-release metoprolol 50 mg three times daily resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.
10.3 Digitalis, Clonidine, and Calcium Channel Blockers
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 [see Warnings and Precautions].
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].
In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol succinate 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 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, 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, β1-blockade is comparable and dose-related. 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 administration.
Pediatrics: The pharmacokinetic profile of metoprolol succinate 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.
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: TOPROL-XL, by ASTRAZENECA.
b) Generic drugs: Metoprolol succinate, by various manufacturers.
2) How Supplied:
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP (by WOCKHARDT), are white, biconvex, filmcoated, and scored.
* The 25 mg tablet is scored on both sides.
3) Storage: Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature].