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 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 accordingly. Metoprolol succinate appears as a white to off-white, fine crystalline powder with a molecular weight of 652.8. It is freely soluble in water, soluble in methanol, sparingly soluble in alcohol, and slightly soluble in isopropyl alcohol.

Inactive ingredients in the formulation include microcrystalline cellulose, ethyl cellulose, triethyl citrate, methacrylic acid co-polymer dispersion, talc, polyethylene glycol, hypromellose, titanium dioxide, silicified microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate.

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, which in turn reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

In addition, metoprolol succinate is indicated for the management of angina pectoris.

For heart failure, this medication 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 drug.

Dosage and Administration

Metoprolol succinate extended-release tablets are to be administered once daily. Dosing should be 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 succinate extended-release tablets should be used.

Contraindications

Use of this product is contraindicated in the following situations:

• Patients with known hypersensitivity to any components of the product, due to the risk of severe allergic reactions.

• Individuals with severe bradycardia, as this condition may be exacerbated by the product's effects on heart rate.

• Patients exhibiting heart block greater than first degree, which may lead to significant cardiac complications.

• Individuals in cardiogenic shock, as the product may worsen hemodynamic instability.

• Patients with decompensated cardiac failure, where the product could further compromise cardiac function.

• Individuals with sick sinus syndrome who do not have a pacemaker, due to the potential for life-threatening arrhythmias.

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 potential for exacerbating respiratory conditions. For individuals diagnosed with pheochromocytoma, therapy should be initiated with an alpha blocker before considering beta blocker treatment.

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, which could delay 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 the usual doses of epinephrine when treated for 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 the safe use of this medication; however, ongoing clinical assessment is crucial to ensure patient safety and efficacy of treatment.

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. For patients with pheochromocytoma, it is advised to initiate therapy with an alpha blocker before considering beta-blocker treatment.

In the context of major surgery, it is recommended to avoid the initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac procedures, as this has been associated with bradycardia, hypotension, stroke, and death. Chronic beta-blocker therapy should not routinely be withdrawn prior to surgery. Furthermore, patients with diabetes should be aware that beta blockers may mask the tachycardia associated with hypoglycemia.

Patients with hepatic impairment and those with thyrotoxicosis should be monitored closely, as abrupt withdrawal in the latter may precipitate a thyroid storm. Anaphylactic reactions have also been noted, 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 is advised when administering these agents concomitantly with calcium channel blockers of the verapamil and diltiazem type due to significant inotropic and chronotropic effects.

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, potentially leading to enhanced pharmacodynamic effects. Clinicians should monitor patients closely for signs of excessive bradycardia or hypotension.

CYP2D6 inhibitors are known to increase the concentration of metoprolol. When these inhibitors are prescribed alongside metoprolol, dosage adjustments may be necessary, and careful monitoring of the patient's response to therapy is recommended to avoid adverse effects.

The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers, including metoprolol, can elevate the risk of bradycardia. It is advisable to monitor heart rate and blood pressure closely in patients receiving these combinations to ensure safety.

Additionally, beta-blockers, such as metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Clinicians should consider a gradual tapering of clonidine to mitigate this risk and monitor blood pressure during the transition.

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 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 the 1.0 mg/kg and 2.0 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 tablets have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies of metoprolol succinate extended-release tablets in hypertension did not include a sufficient number of subjects aged 65 and over to determine whether these patients respond differently compared to 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 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 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 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, 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. Therefore, the use of metoprolol tartrate during pregnancy should be considered only if the potential benefits clearly outweigh the risks. Healthcare professionals are advised to exercise caution and evaluate the necessity of this medication in pregnant patients or those of childbearing potential.

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 tablet 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.

Hepatic Impairment

Patients with hepatic impairment may require careful consideration regarding the use of this medication. It is essential to refer to the full prescribing information for comprehensive details on dosage adjustments and monitoring requirements specific to this population.

In patients with compromised liver function, the pharmacokinetics of the drug may be altered, necessitating modifications to the standard dosing regimen. Close monitoring of liver function tests is recommended to assess the patient's hepatic status and to guide treatment decisions.

Healthcare providers should evaluate the severity of hepatic impairment and adjust the dosage accordingly, ensuring that the benefits of treatment outweigh any potential risks associated with altered drug metabolism. Regular follow-up and reassessment of liver function are advised to ensure patient safety and therapeutic efficacy.

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. 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:

Bradycardia

For bradycardia, intravenous atropine should be administered, with doses repeated as necessary to achieve the desired effect. If the response to atropine is inadequate, intravenous isoproterenol or other positive chronotropic agents may be considered. Additionally, the need for transvenous pacemaker insertion should be evaluated.

Hypotension

Management of hypotension should focus on treating the underlying bradycardia. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be warranted to stabilize blood pressure.

Bronchospasm

In cases of bronchospasm, the administration of a beta-2-agonist, such as albuterol via inhalation, or an oral theophylline derivative is recommended to alleviate respiratory distress.

Cardiac Failure

For patients experiencing cardiac failure, the use of diuretics or digoxin may be appropriate for managing congestive heart failure. In instances of cardiogenic shock, intravenous dobutamine, isoproterenol, or glucagon should be considered as potential therapeutic options.

While there is limited experience with the use of 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 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. However, 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. Similarly, metoprolol succinate was also negative in a Salmonella/mammalian-microsome mutagenicity test.

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

During post-approval use of metoprolol succinate extended-release tablets and immediate-release metoprolol, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular events include cold extremities, arterial insufficiency (typically of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory reactions consist of wheezing (bronchospasm) and dyspnea. Central nervous system effects reported include confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia. Gastrointestinal disturbances encompass nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitivity reactions have included pruritus.

Additional miscellaneous reactions reported include musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosensitivity, and taste disturbance.

Furthermore, there are potential adverse reactions not specifically listed above that have been associated with other beta-adrenergic blocking agents and should be considered as potential reactions to metoprolol succinate extended-release tablets. These include central nervous system effects such as reversible mental depression progressing to catatonia, and an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic reactions may involve agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. Hypersensitivity reactions may also include laryngospasm and respiratory distress.

Patient Counseling

Healthcare providers should advise patients to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. Instruct patients that if they miss a dose, they should take only the next scheduled dose and not double up on doses.

It is important to inform patients that they should not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician. Providers should emphasize the need for caution, advising 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, they 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 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 Wockhardt Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)