Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available in the form of extended-release tablets. These tablets are specifically formulated to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. The formulation consists of a multiple unit system containing metoprolol succinate in numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The tablets are available in strengths of 23.75 mg, 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, which correspond to 25 mg, 50 mg, 100 mg, and 200 mg of metoprolol tartrate, USP, respectively. The chemical name of metoprolol succinate is (±)1-(isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is represented as follows:

Metoprolol succinate appears as a white crystalline powder with a molecular weight of 652.8 g/mol. It is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, and slightly soluble in dichloromethane and 2-propanol. It is practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane. The inactive ingredients include silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, and paraffin.

Uses and Indications

Metoprolol Succinate is indicated for the treatment of hypertension, angina pectoris, and heart failure.

This drug is indicated for hypertension to lower blood pressure, thereby reducing the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the management of angina pectoris. Additionally, Metoprolol Succinate is indicated for the treatment of stable, symptomatic heart failure classified as NYHA Class II or III, which may be of ischemic, hypertensive, or cardiomyopathic origin.

There are no teratogenic or nonteratogenic effects associated with Metoprolol Succinate.

Dosage and Administration

Metoprolol succinate should be administered once daily, with dosing individualized based on the patient's clinical condition and response.

For heart failure, the recommended starting dose is either 12.5 mg or 25 mg, which may be doubled every two weeks to the highest dose tolerated, not exceeding 200 mg per day.

In the management of hypertension, the usual initial dosage ranges from 25 mg to 100 mg once daily. The dosage may be increased at weekly intervals or longer until optimal blood pressure reduction is achieved. It is important to note that dosages above 400 mg per day have not been studied.

For angina pectoris, the usual initial dosage is 100 mg once daily. The dosage should be gradually increased at weekly intervals until the optimum clinical response is obtained or until there is an unacceptable level of bradycardia. Similar to hypertension, dosages above 400 mg per day have not been studied.

When switching from immediate-release metoprolol to metoprolol succinate extended-release tablets, the same total daily dose of metoprolol succinate extended-release should be used.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to any of its components.

Additionally, it should not be administered to individuals with severe bradycardia, heart block greater than first degree, or cardiogenic shock.

Patients experiencing decompensated cardiac failure or those with sick sinus syndrome who do not have a pacemaker are also contraindicated for use.

Warnings and Precautions

Worsening cardiac failure may occur in patients with pre-existing heart conditions. It is essential to monitor these patients closely for any signs of deterioration in cardiac function (5.2).

In individuals with bronchospastic disease, the use of beta blockers is contraindicated due to the potential for exacerbating respiratory symptoms (5.3). For patients diagnosed with pheochromocytoma, it is critical to initiate therapy with an alpha blocker prior to the introduction of beta blockers to avoid hypertensive crises (5.4).

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. This is due to the associated risks of bradycardia, hypotension, stroke, and even death. It is also advised not to routinely withdraw chronic beta blocker therapy before surgery (5.5, 6.1).

Patients with diabetes should be aware that beta blockers may mask the tachycardic response typically seen with hypoglycemia, potentially delaying recognition of this condition (5.6). Additionally, caution is warranted in patients with hepatic impairment, as the pharmacokinetics of beta blockers may be altered (5.7).

In cases of thyrotoxicosis, abrupt withdrawal of beta blockers can precipitate a thyroid storm, necessitating careful management of therapy in these patients (5.8). Furthermore, individuals with a history of anaphylactic reactions may not respond to standard doses of epinephrine, which is critical for treating allergic reactions (5.9).

Patients with peripheral vascular disease should be monitored closely, as beta blockers can exacerbate symptoms of arterial insufficiency (5.10). When used in conjunction with calcium channel blockers, particularly verapamil and diltiazem, significant inotropic and chronotropic effects may occur. Therefore, caution is advised when administering these agents together (5.11).

It is important to note that abrupt cessation of beta-blocking therapy can lead to exacerbations of angina pectoris and myocardial infarction. Patients should be counseled against discontinuing therapy without consulting their healthcare provider (5.1).

Side Effects

Patients receiving treatment with metoprolol succinate extended-release tablets may experience a range of adverse reactions. The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash.

Serious adverse reactions have been noted, particularly in specific patient populations. Patients with ischemic heart disease are at risk for exacerbations of angina pectoris and myocardial infarction following abrupt cessation of therapy with beta-blocking agents. Therefore, it is crucial to advise patients against interrupting or discontinuing therapy without consulting their physician. Additionally, worsening cardiac failure may occur in patients with heart failure, and those with bronchospastic disease should avoid beta blockers altogether. In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha blocker before considering beta-blocker treatment.

Caution is advised for patients undergoing major surgery, as the initiation of high-dose extended-release metoprolol has been associated with bradycardia, hypotension, stroke, and death. It is also important not to routinely withdraw chronic beta blocker therapy prior to surgery. Patients with diabetes should be aware that beta blockers may mask the tachycardia associated with hypoglycemia. Furthermore, patients with hepatic impairment require careful monitoring, and abrupt withdrawal in those with thyrotoxicosis may precipitate a thyroid storm.

Anaphylactic reactions have been reported, with patients potentially being unresponsive to the usual doses of epinephrine used to treat allergic reactions. Additionally, peripheral vascular disease may be aggravated by beta blocker therapy, and caution should be exercised in patients concurrently treated with calcium channel blockers.

Contraindications for the use of metoprolol include known hypersensitivity to the product components, severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, and sick sinus syndrome without a pacemaker.

In cases of overdosage, patients may present with severe bradycardia, hypotension, and cardiogenic shock. Other clinical manifestations can include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, nausea, and vomiting.

Drug Interactions

Catecholamine-depleting drugs may exhibit an additive effect when administered concurrently with beta-blocking agents, potentially leading to enhanced pharmacological effects.

CYP2D6 inhibitors are known to increase the concentration of metoprolol, necessitating careful monitoring of metoprolol levels and potential dosage adjustments to mitigate the risk of adverse effects.

The concomitant use of beta-blockers, such as metoprolol, with glycosides, clonidine, diltiazem, or verapamil may elevate the risk of bradycardia. Clinicians should monitor heart rate and consider dosage adjustments of beta-blockers in patients receiving these combinations.

Additionally, beta-blockers, including metoprolol, may worsen rebound hypertension following the withdrawal of clonidine. It is advisable to monitor blood pressure closely in patients transitioning off clonidine therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Metoprolol Succinate, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to receive either placebo or one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1.0, or 2.0 mg/kg once daily) over a 4-week period. The study did not achieve its primary endpoint of demonstrating a dose response for reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for reduction in diastolic blood pressure (DBP) and significant changes in SBP when comparing 1 mg/kg and 2 mg/kg doses to placebo.

The mean placebo-corrected reductions in SBP ranged from 3 to 6 mmHg, while reductions in DBP ranged from 1 to 5 mmHg. Additionally, the mean reduction in heart rate was between 5 to 7 bpm, with some individuals experiencing considerably greater reductions.

No clinically relevant differences in the adverse event profile were observed between pediatric patients aged 6 to 16 years and adult patients. It is important to note that the safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies of metoprolol succinate extended-release tablets in the treatment of hypertension did not include a sufficient number of subjects aged 65 and older to determine whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not identified significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets, 50% of the participants were aged 65 years and older, and 12% were aged 75 years and older. The findings from this trial indicated no notable differences in efficacy or the rate of adverse reactions between older and younger patients.

Given the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, it is generally recommended to initiate treatment with a low starting dose in geriatric patients. This approach helps to ensure safety and minimize the risk of adverse effects in this population. Regular monitoring is advised to assess the patient's response and adjust the dosage as necessary.

Pregnancy

Metoprolol tartrate is classified as a Pregnancy Category C medication. Animal studies have demonstrated that metoprolol tartrate can increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times the daily dose of 200 mg in a 60-kg patient, indicating potential risks to fetal outcomes. Additionally, distribution studies in mice have confirmed fetal exposure when metoprolol tartrate is administered to pregnant animals.

While these studies have not shown evidence of impaired fertility or teratogenicity, there are no adequate and well-controlled studies in pregnant women to fully assess the drug's safety profile during pregnancy. Therefore, healthcare professionals should consider the potential risks and benefits before prescribing metoprolol tartrate to pregnant patients, using this medication only if clearly needed.

Lactation

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.

Healthcare professionals should consider possible infant exposure when metoprolol succinate is administered to a nursing woman.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment may require careful consideration regarding dosage adjustments and monitoring. It is essential to evaluate liver function prior to initiating treatment and to monitor liver enzymes regularly throughout the course of therapy.

In patients with compromised liver function, dosage modifications may be necessary to mitigate the risk of adverse effects and ensure therapeutic efficacy. Clinicians should assess the severity of hepatic impairment and adjust the dosage accordingly, as outlined in the prescribing information.

Regular monitoring of liver function tests, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), is recommended to detect any potential hepatotoxicity early. If significant elevations in liver enzymes are observed, further evaluation and potential discontinuation of therapy may be warranted.

Overall, a thorough understanding of the patient's hepatic status is crucial for optimizing treatment outcomes while minimizing risks associated with hepatic impairment.

Overdosage

Overdosage of metoprolol succinate extended-release tablets can result in a range of serious clinical manifestations. The signs and symptoms associated with an overdose may include severe bradycardia, hypotension, and cardiogenic shock. Additional clinical presentations may encompass atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

In the event of an overdose, it is crucial to consider intensive care management for the patient. Those with underlying conditions such as myocardial infarction or heart failure may experience significant hemodynamic instability. It is advisable to consult with a regional poison control center and a medical toxicologist for guidance on management. Notably, beta-blocker overdose can lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Management strategies should be tailored based on the pharmacologic actions of metoprolol. For bradycardia, the need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and conduction disorders. In cases of hypotension, it is essential to treat the underlying bradycardia and consider the administration of intravenous vasopressors, such as dopamine or norepinephrine.

For patients experiencing heart failure and shock, appropriate treatment may involve volume expansion, the injection of glucagon (if necessary, followed by an intravenous infusion), and the intravenous administration of adrenergic drugs such as dobutamine. In instances of vasodilation, α1 receptor agonistic drugs may be added to the treatment regimen.

Bronchospasm resulting from an overdose can typically be managed with bronchodilators. While there is limited experience with the use of hemodialysis for the removal of metoprolol, it is important to note that metoprolol is not highly protein-bound, which may influence the decision to utilize this method in overdose scenarios.

Nonclinical Toxicology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/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 benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug-related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m² basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-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 for any type of tumor.

All genotoxicity tests performed on metoprolol tartrate, including a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei, were negative. Additionally, metoprolol succinate was also evaluated in a Salmonella/mammalian-microsome mutagenicity test, which yielded negative results.

No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m² basis, the daily dose of 200 mg in a 60-kg patient.

Postmarketing Experience

No postmarketing experience details are available in the provided data.

Patient Counseling

Patients should be advised to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. In the event that a dose is missed, patients should take only the next scheduled dose and should not double the dose. It is important for patients to understand that they should not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician.

Healthcare providers should inform patients to avoid operating automobiles and machinery or engaging in other tasks that require alertness until their response to therapy with metoprolol succinate extended-release tablets has been determined. Patients should be instructed to contact their physician if they experience any difficulty in breathing. Additionally, patients should inform their physician or dentist prior to any type of surgery that they are taking metoprolol succinate extended-release tablets.

For patients with heart failure, it is crucial to advise them to consult their physician if they experience signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) as outlined by the United States Pharmacopeia (USP) guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients should be advised not to interrupt therapy without consulting their physician. Clinicians should ensure that bronchodilators, including beta-agonists, are readily available or administered concomitantly for patients with bronchospastic disease to manage potential exacerbations effectively.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Metoprolol Succinate as submitted by Lannett Company, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)