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. The tablets contain 23.75, 47.5, 95, and 190 mg of metoprolol succinate, which is equivalent to 25, 50, 100, and 200 mg of metoprolol tartrate, USP, respectively. The chemical name of metoprolol succinate is (±)1-(isopropyl amino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt). It is classified as a white to off-white powder with a molecular weight of 652.8 g/mol. Metoprolol succinate is freely soluble in water, soluble in methanol, sparingly soluble in alcohol, and slightly soluble in isopropyl alcohol. The inactive ingredients in the formulation include acetyl tributyl citrate, carnauba wax, colloidal silicon dioxide, ethylcellulose, glyceryl dibehenate, hydroxypropyl cellulose, hypromellose, Microcrystalline cellulose PH 105, Microcrystalline cellulose PH 102, polyethylene glycol, sodium stearyl fumarate, and titanium dioxide.

Uses and Indications

Metoprolol succinate is indicated for the treatment of hypertension, angina pectoris, and heart failure. In patients with hypertension, this medication is utilized to lower blood pressure, thereby reducing the risk of both fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions. For patients experiencing angina pectoris, metoprolol succinate serves to alleviate symptoms associated with this condition. Additionally, in the context of heart failure, this drug is indicated to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with metoprolol succinate.

Dosage and Administration

The medication is to be administered once daily. Dosing should be titrated at weekly or longer intervals as needed and tolerated.

For the management of hypertension, the starting dose is 25 to 100 mg. In cases of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dosing should be either 12.5 or 25 mg.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, it is essential to use the same total daily dose of metoprolol succinate extended-release tablets as the immediate-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, including those with greater than first-degree heart block or sick sinus syndrome without a pacemaker. The product is also contraindicated in cases of cardiogenic shock or decompensated heart failure due to the potential for exacerbating these conditions.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may lead to exacerbation of myocardial ischemia. Therefore, it is crucial for healthcare professionals to consider the potential risks associated with sudden discontinuation of treatment, particularly in patients with underlying cardiovascular conditions.

In patients with heart failure, there is a risk of worsening cardiac function. Continuous monitoring of cardiac status is recommended to identify any deterioration in heart failure symptoms.

For individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the potential for bronchospasm. Alternative therapies should be considered to manage these patients effectively.

Concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may increase the risk of bradycardia. Close monitoring of heart rate and rhythm is advised when these medications are used together.

In patients diagnosed with pheochromocytoma, it is essential to initiate therapy with an alpha blocker prior to starting beta-blocker treatment to prevent hypertensive crises.

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. However, it is not routinely necessary to withdraw chronic beta-blocker therapy prior to surgery, as this may lead to adverse cardiovascular events.

Patients on beta-blockers may experience an increased risk of hypoglycemia, and these medications can mask the early warning signs of low blood sugar. Regular monitoring of blood glucose levels is recommended, especially in diabetic patients.

In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, a life-threatening condition. Therefore, careful management and gradual tapering of the medication are advised.

For patients with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended to assess any worsening of symptoms.

Lastly, it is important to note that patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used for the treatment of allergic reactions. Healthcare professionals should be aware of this potential interaction and consider alternative treatment strategies in such scenarios.

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. Abrupt cessation of therapy may exacerbate myocardial ischemia, and worsening cardiac failure may occur in patients with heart failure. In individuals with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbation of symptoms. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia. In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha blocker.

During major surgery, it is advised to avoid the initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac procedures, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery. Additionally, patients may experience an increased risk of hypoglycemia, which can mask early warning signs. In those with thyrotoxicosis, abrupt withdrawal may precipitate a thyroid storm. Peripheral vascular disease may be aggravated, leading to worsened symptoms of arterial insufficiency. Furthermore, patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Known hypersensitivity to the product components is a contraindication for use. Severe bradycardia, defined as greater than first-degree heart block or sick sinus syndrome without a pacemaker, as well as cardiogenic shock or decompensated heart failure, are also serious concerns.

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

CYP2D6 inhibitors are known to potentially increase the concentration of metoprolol. Clinicians should consider monitoring patients for increased effects of metoprolol when these inhibitors are co-administered, as dosage adjustments may be necessary based on clinical response.

Additionally, it is important to note that beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Careful management and monitoring of blood pressure are recommended in patients transitioning from clonidine to beta-blocker therapy to mitigate this risk.

No further drug interactions or interactions with laboratory tests have been identified.

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

In a clinical study involving 144 hypertensive pediatric patients aged 6 to 16 years, participants were randomized to receive either placebo or one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1, or 2 mg/kg once daily) for a duration of 4 weeks. The safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age.

No clinically relevant differences in the adverse event profile were observed between pediatric patients aged 6 to 16 years and adult patients, indicating a similar safety profile across these populations.

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

Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta-blockers, including metoprolol. These findings are limited by methodological issues such as retrospective design and the concomitant use of other medications, which may confound the results.

Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, including the need for cesarean section and postpartum hemorrhage. Additionally, hypertension poses a fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed.

In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, which is approximately 24 times the daily dose of 200 mg in a 60-kg patient on a mg/m² basis. However, no fetal abnormalities were observed when pregnant rats received metoprolol orally at doses up to 200 mg/kg/day, equivalent to 10 times the daily dose of 200 mg in a 60-kg patient.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Therefore, it is recommended that neonates be observed and managed accordingly. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown, but all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

Limited available data from published literature report that metoprolol is present in human milk. The estimated daily infant dose of metoprolol received from breast milk ranges from 0.05 mg to less than 1 mg, with an estimated relative infant dosage of 0.5% to 2% of the mother's weight-adjusted dosage.

No adverse reactions of metoprolol on the breastfed infant have been identified. However, it is recommended that healthcare professionals monitor the breastfed infant for bradycardia and other symptoms of beta blockade, such as listlessness or hypoglycemia.

There is no information regarding the effects of metoprolol on milk production. In a small study involving three mothers (at least 3 months postpartum) who took metoprolol of unspecified amounts, breast milk was collected every 2 to 3 hours over one dosage interval. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17 to 158.7), with an average relative infant dosage of 0.5% of the mother's weight-adjusted dosage. Additionally, in two women taking unspecified amounts of metoprolol, milk samples taken after one dose indicated that the estimated amount of metoprolol and alpha-hydroxy metoprolol in breast milk was less than 2% of the mother's weight-adjusted dosage.

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 have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Signs and symptoms of metoprolol succinate overdose may manifest as severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal disturbances such as nausea and vomiting.

Management of an overdose may necessitate intensive care, particularly in patients with underlying conditions such as myocardial infarction or heart failure, due to the risk of hemodynamic instability. It is important to note that beta-blocker overdose can result in significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

In cases of bradycardia and conduction disorders, healthcare professionals should evaluate the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker. For hypotension associated with overdose, addressing the underlying bradycardia is crucial, and intravenous vasopressor infusion, such as dopamine or norepinephrine, should be considered.

Heart failure and shock resulting from an overdose may be managed through volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. Additionally, bronchospasm that occurs as a consequence of overdose can typically be reversed with the use of bronchodilators.

It is important to note that hemodialysis is unlikely to facilitate the elimination of metoprolol in overdose situations, underscoring the need for comprehensive supportive care and monitoring.

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 documented several adverse reactions, including bradycardia, hypotension, and exacerbation of heart failure. Additional adverse reactions reported include dizziness, fatigue, and depression. Severe allergic reactions, such as anaphylaxis and angioedema, have also been noted.

Instances of liver enzyme elevations and other hepatic events have been reported. Cases of pulmonary embolism and thrombosis have emerged in the postmarketing setting. There are reports of worsening of pre-existing psoriasis, as well as visual disturbances, including blurred vision and dry eyes. Furthermore, postmarketing data indicate a potential association with an increased risk of diabetes mellitus.

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 notice any signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath. Patients or caregivers should also be informed about the risk of hypoglycemia when metoprolol succinate extended-release tablets are administered to patients who are fasting or experiencing vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia effectively.

Storage and Handling

The product is supplied in a packaging configuration of 30 units per blister pack. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15 to 30°C (59 to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)