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. Each tablet contains metoprolol succinate in a multiple unit system composed of numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The extended-release tablets are available in two strengths: 95 mg and 190 mg of metoprolol succinate, which are equivalent to 100 mg and 200 mg of metoprolol tartrate, 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 accordingly. Metoprolol succinate USP appears as a white to off-white powder with a molecular weight of 652.8. It is freely soluble in water and soluble in methanol.

Inactive ingredients in the formulation include acetyl tributyl citrate, colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, methylene chloride, microcrystalline cellulose, polyethylene glycol, sodium stearyl fumarate, talc, and titanium dioxide.

Uses and Indications

Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension, angina pectoris, and heart failure.

This drug is indicated for the management of hypertension to lower blood pressure, thereby reducing the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Additionally, it is indicated for the treatment of angina pectoris.

Metoprolol succinate is also 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 this medication.

Dosage and Administration

Metoprolol succinate extended-release 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, the same total daily dose of metoprolol should be used for the extended-release formulation.

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

Following abrupt cessation of therapy with beta-blocking agents, patients may experience exacerbations of angina pectoris and myocardial infarction. It is imperative to advise patients against interrupting or discontinuing therapy without consulting their physician.

In patients with heart failure, there is a risk of worsening cardiac function. Therefore, careful monitoring is essential in this population.

Beta-blockers should be avoided in individuals with bronchospastic disease due to the potential for exacerbating respiratory conditions. In cases of pheochromocytoma, therapy should be initiated with an alpha blocker prior to the introduction of beta-blockers.

For patients undergoing non-cardiac surgery, the initiation of high-dose extended-release metoprolol is contraindicated, as it has been associated with serious adverse events, including bradycardia, hypotension, stroke, and death. It is generally not recommended to withdraw chronic beta-blocker therapy before surgery.

Patients with diabetes should be informed that beta-blockers may mask the tachycardia typically associated with hypoglycemia, necessitating careful blood glucose monitoring. Additionally, caution is advised in patients with hepatic impairment, as the pharmacokinetics of beta-blockers may be altered.

In individuals with thyrotoxicosis, abrupt withdrawal of beta-blockers can precipitate a thyroid storm, which is a life-threatening condition. Furthermore, patients with a history of anaphylactic reactions may not respond to standard doses of epinephrine used for treatment, highlighting the need for alternative management strategies in such cases.

Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency when treated with beta-blockers. Caution is also warranted when administering beta-blockers in conjunction with calcium channel blockers of the verapamil and diltiazem types, due to their significant inotropic and chronotropic effects.

Healthcare professionals should remain vigilant in monitoring these patients and consider the outlined warnings and precautions to ensure safe and effective use of beta-blocking agents.

Side Effects

Patients receiving treatment 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 also been noted. Patients may experience worsening cardiac failure, particularly in those with pre-existing heart conditions. Abrupt cessation of therapy with beta-blocking agents can lead to exacerbations of angina pectoris and myocardial infarction; therefore, patients should be warned against discontinuing therapy without consulting their physician. In patients with bronchospastic disease, beta-blockers should be avoided due to the risk of exacerbating respiratory symptoms.

In the context of major surgery, caution is advised. The initiation of high-dose extended-release metoprolol should be avoided in patients undergoing non-cardiac surgery, as it has been associated with bradycardia, hypotension, stroke, and death. It is also recommended 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. Additionally, caution is advised for patients with hepatic impairment, and those with thyrotoxicosis should be monitored closely, as abrupt withdrawal may precipitate a thyroid storm. Anaphylactic reactions may occur, and patients may be unresponsive to the usual doses of epinephrine used to treat such reactions. Furthermore, peripheral vascular disease may be aggravated by beta-blocker therapy.

Patients receiving concurrent treatment with calcium channel blockers of the verapamil and diltiazem type should be monitored closely due to potential interactions.

Contraindications for the use of this medication include known hypersensitivity to its 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. This interaction necessitates careful monitoring of the patient's cardiovascular status, as the combined effects may lead to significant hypotension or bradycardia.

CYP2D6 inhibitors are known to potentially increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol when initiating or discontinuing CYP2D6 inhibitors to avoid adverse effects associated with elevated drug levels.

The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers, including metoprolol, may heighten the risk of bradycardia. It is advisable to monitor heart rate and blood pressure closely in patients receiving these combinations, and dosage adjustments may be warranted based on the patient's response.

Additionally, beta-blockers, such as metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Clinicians should be cautious when discontinuing clonidine in patients receiving beta-blockers and consider a gradual tapering of clonidine to mitigate this risk.

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 (0.2, 1, or 2 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 observed to be between 5 to 7 beats per minute, with some individuals experiencing considerably greater reductions.

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

Geriatric Use

Clinical studies of metoprolol succinate extended-release in hypertension did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported 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, 50% (990) of the participants were aged 65 years and older, and 12% (238) 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 greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in geriatric patients, it is generally recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy in elderly patients.

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, based on a mg/m² comparison. Additionally, distribution studies in mice indicate that the fetus is exposed to metoprolol tartrate when 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. Given that animal reproduction studies may not always predict human outcomes, metoprolol tartrate should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Healthcare professionals are advised to carefully consider the necessity of this medication in pregnant patients.

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 extended-release is administered to a nursing woman.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be warranted in these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment may experience altered pharmacokinetics of the drug, necessitating careful consideration of dosage adjustments and monitoring. It is recommended that healthcare providers assess liver function prior to initiating treatment and periodically thereafter.

In patients with mild to moderate hepatic impairment, dosage adjustments may be required to avoid potential toxicity. Close monitoring of liver function tests is advised to ensure patient safety and therapeutic efficacy.

For patients with severe hepatic impairment, the use of this medication is contraindicated due to the increased risk of adverse effects and insufficient data to support safe use in this population.

Healthcare providers should remain vigilant in monitoring for signs of liver dysfunction and adjust treatment plans accordingly to mitigate risks associated with compromised liver function.

Overdosage

Overdosage of metoprolol succinate extended-release 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, necessitating close monitoring and intervention. Consultation with a regional poison control center and a medical toxicologist is recommended to guide treatment decisions. It is important to note that 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, treating the underlying bradycardia is essential, and intravenous vasopressor infusion, such as dopamine or norepinephrine, may be warranted.

For patients experiencing heart failure and shock, appropriate treatment may include volume expansion, the injection of glucagon (if necessary, followed by an intravenous infusion), and the 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 reversed with the use of bronchodilators. While there is limited experience with hemodialysis for the removal of metoprolol, it is noteworthy that metoprolol is not highly protein-bound, which may influence the decision to utilize this method in severe cases.

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

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. These include bradycardia, heart block, hypotension, dizziness, and fatigue. Additional reported events encompass depression, shortness of breath, peripheral edema, rash, pruritus, nausea, vomiting, diarrhea, dry mouth, insomnia, and nightmares.

Furthermore, sexual dysfunction, anaphylactic reactions, hepatic enzyme elevations, thrombocytopenia, alopecia, and exacerbation of psoriasis have also been documented. There have been reports of drug interactions that may lead to increased effects of metoprolol.

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 the use of 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 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP) guidelines. 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. No further information is available regarding laboratory tests, abuse potential, route, method, and frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)