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: 23.75 mg and 47.5 mg of metoprolol succinate, which are equivalent to 25 mg and 50 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 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. The formulation includes several inactive ingredients: acetyl tributyl citrate, colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, methylene chloride, microcrystalline cellulose, polyethylene glycol 6000, prosolv, 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 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, originating from ischemic, hypertensive, or cardiomyopathic causes.

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 response and tolerability.

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 the treatment of 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 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 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

Worsening cardiac failure may occur in patients receiving treatment. It is essential for healthcare professionals to monitor patients closely for any signs of deterioration in cardiac function.

In patients with bronchospastic disease, beta-blockers should be avoided due to the risk of exacerbating respiratory conditions. For individuals diagnosed with pheochromocytoma, therapy should be initiated with an alpha blocker before considering the use of beta-blockers.

High-dose extended-release metoprolol should not be initiated in patients undergoing non-cardiac surgery, as it has been associated with serious adverse events, including bradycardia, hypotension, stroke, and death. It is also advised not to routinely withdraw chronic beta-blocker therapy prior to surgical procedures.

Healthcare providers should be aware that beta-blockers may mask tachycardia in diabetic patients experiencing hypoglycemia, potentially delaying recognition and treatment of this condition. Special considerations are warranted for patients with hepatic impairment, as their response to treatment may differ.

Abrupt withdrawal of beta-blockers in patients with thyrotoxicosis can precipitate a thyroid storm, a life-threatening condition. Additionally, patients may exhibit unresponsiveness to standard doses of epinephrine used for treating allergic reactions, necessitating careful monitoring and potential adjustment of treatment protocols.

In patients with peripheral vascular disease, beta-blockers can aggravate symptoms of arterial insufficiency. Caution is advised when administering beta-blockers in conjunction with calcium channel blockers of the verapamil and diltiazem type, as this combination may lead to significant inotropic and chronotropic effects.

Following abrupt cessation of therapy with beta-blocking agents, there is a risk of exacerbations of angina pectoris and myocardial infarction. Patients should be warned against interrupting or discontinuing therapy without consulting their physician.

No specific laboratory tests are recommended for monitoring during treatment. However, healthcare professionals should remain vigilant and assess patients regularly for any adverse effects or complications associated with therapy.

Side Effects

Patients may experience a range of adverse reactions while undergoing treatment. The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash.

Serious adverse reactions warrant particular attention. A warning is issued regarding ischemic heart disease, as abrupt cessation of therapy with beta-blocking agents can lead to exacerbations of angina pectoris and myocardial infarction. Patients should be cautioned against interrupting or discontinuing therapy without consulting their physician. Additionally, worsening cardiac failure may occur in patients with heart failure, and beta-blockers should be avoided in individuals with bronchospastic disease. In cases of pheochromocytoma, it is advised to initiate therapy with an alpha blocker before considering beta-blocker treatment.

Patients undergoing major surgery should avoid the initiation of high-dose extended-release metoprolol, 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. Furthermore, patients with diabetes should be aware that beta-blockers may mask tachycardia associated with hypoglycemia. Caution is advised for patients with hepatic impairment, 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 for treatment. Peripheral vascular disease may be aggravated by beta-blocker therapy, and caution should be exercised in patients receiving both beta-blockers and calcium channel blockers of the verapamil and diltiazem type.

Contraindications for the use of this medication include known hypersensitivity to 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. This combination could potentially enhance the pharmacological effects of beta-blockers, necessitating careful monitoring of the patient's response and possible dosage adjustments.

CYP2D6 inhibitors are known to increase the concentration of metoprolol. Clinicians should consider monitoring metoprolol levels and adjusting the dosage accordingly to avoid potential adverse effects associated with elevated drug concentrations.

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 rhythm closely in patients receiving these combinations, and dosage adjustments may be warranted based on clinical response.

Additionally, beta-blockers, such as metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Clinicians should be vigilant in monitoring blood pressure in patients transitioning off clonidine and consider appropriate management strategies 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 the reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for the 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 in 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 these elderly patients respond differently from younger individuals. 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 randomized 1,990 patients with heart failure to metoprolol succinate extended-release, 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 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 receiving metoprolol succinate extended-release.

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 clearly outweigh the risks. 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 advisable in these patients to ensure safety and efficacy.

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 parameters 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. Regular assessment of liver enzymes and other relevant laboratory values is recommended to monitor the patient's hepatic status and adjust treatment as needed.

Healthcare providers should exercise caution when prescribing this medication to patients with hepatic impairment, as the pharmacokinetics may be altered, potentially leading to increased systemic exposure. Close monitoring is advised to ensure patient safety and optimal therapeutic outcomes.

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 managing an overdose, it is crucial to consider intensive care for the patient, particularly for those with underlying conditions such as myocardial infarction or heart failure, as they may experience significant hemodynamic instability. 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

Bradycardia: The initial approach should involve the administration of intravenous atropine, with doses repeated as necessary to achieve the desired effect. If the response to atropine is insufficient, intravenous isoproterenol or other positive chronotropic agents may be considered. Additionally, the need for transvenous pacemaker insertion should be evaluated.

Hypotension: Addressing the underlying bradycardia is essential. In cases where hypotension persists, intravenous vasopressor infusion, such as dopamine or norepinephrine, may be warranted.

Bronchospasm: For bronchospasm, the administration of a beta-2-agonist, such as albuterol via inhalation, or an oral theophylline derivative is recommended.

Cardiac Failure: In instances of congestive heart failure, the use of diuretics or digoxin may be appropriate. For patients experiencing cardiogenic shock, intravenous dobutamine, isoproterenol, or glucagon should be considered.

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 overdose management.

Nonclinical Toxicology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In two-year studies in rats at three oral dosage levels of up to 800 mg/kg/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 tested in a Salmonella/mammalian-microsome mutagenicity test, yielding 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 a range of adverse reactions associated with the use of the medication. These include bradycardia, heart block, hypotension, dizziness, fatigue, depression, shortness of breath, peripheral edema, rash, pruritus, nausea, vomiting, diarrhea, dry mouth, insomnia, nightmares, sexual dysfunction, anaphylactic reactions, hepatic enzyme elevations, thrombocytopenia, alopecia, and exacerbation of psoriasis.

Additionally, there have been reports of increased blood glucose levels, increased triglycerides, and elevated uric acid levels. Rare cases of severe allergic reactions and drug interactions leading to enhanced effects of other medications have also been documented.

The safety profile of metoprolol succinate extended-release tablets continues to be monitored through ongoing postmarketing surveillance.

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 to make up for the missed one. 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 also be instructed to contact their physician if they experience any difficulty in breathing. Additionally, patients must 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 notice any 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)