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 consist of a multiple unit system that contains metoprolol succinate in numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to provide continuous release of metoprolol 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-(isopropyl amino)-3-p-(2-methoxyethyl)phenoxy-2-propanol succinate (2:1) (salt). Metoprolol succinate, USP is characterized as a white crystalline powder with a molecular weight of 652.8 g/mol. It exhibits solubility properties as follows: it is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in dichloromethane and 2-propanol, and practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane.

Inactive ingredients in the formulation include colloidal silicon dioxide, crospovidone, ethylcellulose, hypromellose, lactose monohydrate (25 mg and 50 mg), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, sugar spheres (composed of corn starch and sucrose), talc, titanium dioxide, and triethyl citrate.

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.

In the management of angina pectoris, metoprolol succinate aids in alleviating symptoms associated with this condition. Additionally, it is indicated for patients with heart failure, where it has been shown 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 between 25 mg and 100 mg. In cases of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dose may be either 12.5 mg or 25 mg, depending on the patient's condition and response.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, it is essential to maintain the same total daily dose of metoprolol succinate extended-release tablets as the patient was receiving with 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, healthcare professionals should exercise caution when discontinuing treatment, particularly in patients with a history of ischemic heart disease.

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.

Beta-blockers are contraindicated in individuals with bronchospastic disease, as they may induce bronchospasm. Alternative therapies should be considered for these patients to avoid respiratory complications.

Concomitant use of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may increase the risk of bradycardia. It is essential to monitor heart rate and rhythm closely in patients receiving these combinations to prevent significant bradycardic events.

For patients diagnosed with pheochromocytoma, therapy should be initiated with an alpha-blocker prior to the introduction of beta-blockers to mitigate the risk of hypertensive crises.

In the context of major surgery, particularly non-cardiac procedures, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta-blocker therapy should not be routinely withdrawn 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 advised, especially in diabetic patients.

In individuals with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm. Caution is warranted, and any changes in therapy should be made gradually under close supervision.

For patients with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Careful assessment of vascular status is recommended to ensure that treatment does not worsen the patient's condition.

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 providers should consider alternative dosing strategies or adjunctive therapies in these cases to ensure effective management of anaphylaxis.

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. Worsening cardiac failure may occur in patients with pre-existing heart conditions. Abrupt cessation of therapy can exacerbate myocardial ischemia, and patients with bronchospastic disease should avoid beta-blockers due to the risk of bronchospasm. Additionally, the concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers may increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha-blocker. For those undergoing major surgery, the initiation of high-dose extended-release metoprolol should be avoided, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery.

Patients may also experience an increased risk of hypoglycemia, which can mask early warning signs. In individuals with thyrotoxicosis, abrupt withdrawal of treatment may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

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, as well as nausea and vomiting.

Drug Interactions

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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, or 2 mg/kg once daily) and were followed for 4 weeks. The safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age. In pediatric patients aged 6 to 16 years, no clinically relevant differences in the adverse event profile were observed when compared to adult patients.

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 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 tablets.

Pregnancy

Available data indicate that untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. While 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, there are inconsistent reports regarding intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta-blockers, including metoprolol.

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; however, 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.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and post-partum hemorrhage. Additionally, hypertension elevates the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

It is important to note that stroke volume and heart rate increase during pregnancy, leading to increased cardiac output, particularly during the first trimester. There is also a risk for preterm birth in pregnant women with chronic heart failure during the third trimester.

In summary, while metoprolol has not been conclusively associated with major congenital malformations, careful consideration and monitoring are warranted for pregnant patients receiving this medication.

Lactation

Metoprolol crosses the placenta. Lactating mothers receiving metoprolol should be aware that neonates born to them may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is important to observe breastfed infants for these potential effects and manage them accordingly.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

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 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 overdose may manifest as severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, and impairment of consciousness, which can progress to coma. Additionally, gastrointestinal symptoms such as nausea and vomiting may occur.

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, treatment options may include the administration of atropine, adrenergic-stimulating drugs, or the placement of a pacemaker. Hypotension should be managed by addressing the underlying bradycardia and considering the use of intravenous vasopressors, such as dopamine or norepinephrine.

For patients experiencing heart failure and shock due to overdose, treatment may involve volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. Bronchospasm, which may occur as a result of overdose, can typically be reversed with bronchodilators.

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol in overdose situations, and therefore, alternative management strategies should be prioritized.

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 revealed reports of various adverse reactions associated with the use of the medication. Notable adverse reactions include bradycardia, hypotension, and heart failure. Additional reactions reported encompass dizziness, fatigue, and depression.

Rare cases of severe allergic reactions, including anaphylaxis, have been documented, alongside reports of angioedema and skin reactions such as rash and pruritus. Furthermore, instances of hepatic enzyme elevations have been noted in the postmarketing 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 counsel patients to avoid operating automobiles and machinery or engaging in other tasks that require alertness until the patient's 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. 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 who are vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines.

It is essential to ensure that the product is kept out of the reach of children to maintain safety.

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 BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)