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 capsules. These capsules are specifically formulated to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. The formulation 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 extended-release capsules contain varying amounts of metoprolol free base: 10.24 mg, 20.48 mg, 40.96 mg, and 81.92 mg, which correspond to 23.75 mg, 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, respectively. These amounts are equivalent to 25 mg, 50 mg, 100 mg, and 200 mg of metoprolol tartrate, USP. 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 provided in the accompanying documentation.

Metoprolol succinate, USP appears as a white to off-white powder with a molecular weight of 652.82. It 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 ethyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 6000, sugar spheres (corn starch and sucrose), talc, and triethyl citrate. The capsule shell and imprinting ink are composed of ferric oxide yellow (for 25 mg, 50 mg, and 200 mg), ferrosoferric oxide, gelatin, potassium hydroxide, propylene glycol, shellac, and titanium dioxide.

Uses and Indications

Metoprolol succinate extended-release capsules 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. In patients with heart failure, metoprolol succinate extended-release capsules are indicated to reduce the risk of cardiovascular mortality and heart-failure hospitalization.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

For the management of adult hypertension, the usual initial dosage is 25 to 100 mg administered once daily. Healthcare professionals should titrate the dosage weekly, or longer if necessary, to achieve optimal blood pressure control.

In pediatric patients aged 6 years and older with hypertension, the recommended starting dose is 1 mg/kg once daily, with titration based on the individual response. The maximum initial dose should not exceed 50 mg once daily.

For the treatment of angina pectoris, the usual initial dosage is 100 mg once daily. Titration should occur weekly, guided by the clinical response of the patient.

In cases of heart failure, the recommended starting dose is 25 mg, which may be doubled every two weeks to reach the highest dose tolerated, with a maximum of up to 200 mg.

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, greater than first degree heart block, or sick sinus syndrome in the absence of a pacemaker, due to the potential for exacerbating these conditions.

The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure, as these conditions may lead to serious complications.

Warnings and Precautions

Abrupt cessation of therapy may lead to exacerbation of myocardial ischemia, necessitating careful consideration of discontinuation protocols. Healthcare professionals should be vigilant in monitoring patients for signs of worsening cardiac failure, as this condition may deteriorate during treatment.

In patients with bronchospastic disease, the use of beta blockers is contraindicated due to the potential for exacerbating respiratory symptoms. For individuals diagnosed with pheochromocytoma, it is imperative to initiate therapy with an alpha blocker prior to the introduction of beta blockers to mitigate the risk of hypertensive crises.

When considering the initiation of high-dose extended-release metoprolol, caution is advised. It is recommended to avoid starting this treatment in patients who are already on chronic beta blocker therapy, particularly in the context of surgical procedures. Routine withdrawal of beta blockers before surgery should also be avoided to prevent adverse cardiovascular events.

Healthcare providers should be aware that beta blockers may mask the tachycardia associated with hypoglycemia, which can complicate the management of diabetic patients. Additionally, abrupt withdrawal of beta blockers in patients with thyrotoxicosis poses a significant risk, as it may precipitate a thyroid storm, a life-threatening condition.

Finally, it is important to note that beta blockers may aggravate symptoms of arterial insufficiency, and patients should be monitored closely for any signs of worsening peripheral circulation. Regular assessment and appropriate laboratory tests should be conducted to ensure patient safety throughout the course of treatment.

Side Effects

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

In addition to these common reactions, there are several important considerations regarding the safety profile of the treatment. Abrupt cessation of therapy may exacerbate myocardial ischemia and worsen cardiac failure. Patients with bronchospastic disease should avoid beta blockers, and those with pheochromocytoma should initiate therapy with an alpha blocker. It is also advised to avoid the initiation of high-dose extended-release metoprolol and to refrain from routinely withdrawing chronic beta blocker therapy prior to surgical procedures.

Furthermore, the treatment may mask tachycardia that occurs with hypoglycemia, and abrupt withdrawal in patients with thyrotoxicosis could precipitate a thyroid storm. Symptoms of arterial insufficiency may also be aggravated by the treatment.

Contraindications include known hypersensitivity to the product components, severe bradycardia, greater than first-degree heart block, sick sinus syndrome without a pacemaker, cardiogenic shock, or decompensated heart failure.

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

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 increased bradycardia or hypotension.

In cases where beta-blockers are used, patients may demonstrate reduced responsiveness to standard doses of epinephrine, which is critical for the management of allergic reactions. It is advisable to consider alternative dosing strategies or adjunctive therapies in such scenarios.

The concomitant use of CYP2D6 inhibitors is likely to elevate the plasma concentration of metoprolol, necessitating careful monitoring of the patient for signs of increased beta-blocker effects. Dose adjustments may be required based on clinical response.

Additionally, the co-administration of glycosides, clonidine, diltiazem, or verapamil with beta-blockers can heighten the risk of bradycardia. Clinicians should evaluate the need for dosage modifications and monitor heart rate and blood pressure closely.

It is important to note that beta-blockers, including metoprolol, may worsen rebound hypertension following the discontinuation of clonidine. Patients should be monitored for this effect, and appropriate management strategies should be implemented.

Lastly, alcohol consumption can interfere with the extended-release properties of this product, potentially leading to altered therapeutic effects. Patients should be advised to limit or avoid alcohol intake while on this medication.

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 (0.2, 1, or 2 mg/kg once daily) for a duration of 4 weeks. The safety and effectiveness of metoprolol succinate 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 evaluating metoprolol succinate for hypertension did not include a sufficient number of subjects aged 65 years and older to ascertain whether their responses differ from those of younger patients. However, other clinical experiences in hypertensive patients have not indicated any 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, 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 revealed no notable differences in efficacy or the incidence 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 in elderly patients, it is recommended to initiate treatment with a low starting dose for this population. Careful monitoring and consideration of individual patient factors are essential to ensure safety and efficacy in geriatric patients.

Pregnancy

Available data from published observational studies have not demonstrated an association of adverse developmental outcomes with maternal use of metoprolol during pregnancy. However, it is important to note that 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, such as the need for cesarean section and post-partum 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 accordingly.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that healthcare providers observe neonates for these symptoms and manage them as necessary.

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.

All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

While data from observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy, there have been inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality associated with maternal use of metoprolol. These studies have methodological limitations, including retrospective design, concomitant use of other medications, and unadjusted confounders that may influence the findings, such as the underlying disease in the mother. Consequently, these observational studies cannot definitively establish or exclude any drug-associated risk during pregnancy.

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. There is no information regarding the effects of metoprolol on milk production. For lactating mothers who are slow metabolizers of metoprolol, it is advisable to monitor the breastfed infant for bradycardia and other symptoms of beta blockade, such as dry mouth, skin or eyes, diarrhea, or constipation. In a report involving six mothers taking metoprolol, none reported adverse effects in their breastfed infants.

In a small study, breast milk was collected every 2 to 3 hours over one dosage interval from three mothers (at least 3 months postpartum) who took metoprolol in unspecified amounts. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 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-hydroxymetoprolol 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.

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

Overdosage of metoprolol succinate can result in a range of severe clinical manifestations, necessitating immediate medical intervention.

Signs and Symptoms

Patients experiencing an overdose may present with severe bradycardia, hypotension, and cardiogenic shock. Additional symptoms may include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal disturbances such as nausea and vomiting.

Treatment

Management of metoprolol succinate overdosage should be conducted in an intensive care setting, particularly for patients with underlying conditions such as myocardial infarction or heart failure, who may exhibit significant hemodynamic instability. It is important to note that beta-blocker overdose can lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Bradycardia

In cases of bradycardia, the clinician should assess the necessity for atropine administration, the use of adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction disorders.

Hypotension

Management of hypotension should focus on treating the underlying bradycardia. Consideration should be given to the intravenous infusion of vasopressors, such as dopamine or norepinephrine, to stabilize blood pressure.

Heart Failure and Shock

For patients presenting with heart failure or shock, appropriate treatment may include volume expansion and the administration of glucagon, if indicated, followed by an intravenous glucagon infusion. Additionally, intravenous adrenergic drugs such as dobutamine may be utilized, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm

Bronchospasm associated with metoprolol overdose can typically be reversed with the use of bronchodilators.

Additional Considerations

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 employ this method in severe cases. Prompt recognition and management of symptoms are critical to improving patient outcomes in cases of metoprolol succinate overdosage.

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 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

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Patients with heart failure should be advised to consult their physician if they experience any signs or symptoms indicative of worsening heart failure, such as weight gain or increasing shortness of breath. It is important to inform patients that if they miss a dose of metoprolol succinate extended-release capsules, they should take only the next scheduled dose and not double up on doses.

Patients must be cautioned against interrupting or discontinuing metoprolol succinate extended-release capsules without prior consultation with their physician. Healthcare providers should advise 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 capsules has been fully assessed.

Additionally, patients should be instructed to contact their physician if they experience any difficulty in breathing. It is also essential for patients to inform their physician or dentist about their use of metoprolol succinate extended-release capsules prior to any surgical procedures.

For patients who are breastfeeding, it is crucial to monitor the infant for potential side effects, including bradycardia, dry mouth, skin or eye issues, and gastrointestinal disturbances such as diarrhea or constipation.

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° C to 25° C (68° F to 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 Sun Pharmaceutical Industries Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)