Toprol

Description

TOPROL-XL, metoprolol succinate, is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available in the form of extended-release tablets. The formulation is designed 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 that continuously releases 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 are equivalent 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), and it has a molecular weight of 652.8. Metoprolol succinate, USP appears as a white crystalline powder that is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, and slightly soluble in dichloromethane and 2-propanol. It is practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane. Inactive ingredients include silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, and paraffin.

Uses and Indications

TOPROL-XL, metoprolol succinate, is 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. Additionally, TOPROL-XL is indicated for the management of angina pectoris. In patients with heart failure, this medication is indicated to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with TOPROL-XL.

Dosage and Administration

The medication is administered once daily. Dosing should be titrated at weekly or longer intervals based on patient response and tolerance.

For the management of hypertension, the recommended starting dose is between 25 mg and 100 mg. In cases of angina pectoris, the starting dose is set at 100 mg. For patients with heart failure, the initial dosing should be either 12.5 mg or 25 mg.

When transitioning from immediate-release metoprolol to TOPROL-XL, it is essential to maintain the same total daily dose of TOPROL-XL 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 who do not have a pacemaker. The product is also contraindicated in cases of cardiogenic shock or decompensated heart failure, as these conditions may exacerbate the risks associated with its use.

Warnings and Precautions

Abrupt cessation of therapy may lead to exacerbation of myocardial ischemia; therefore, it is crucial to taper the dosage under medical supervision to mitigate this risk (5.1).

In patients with heart failure, there is a potential for worsening cardiac function. Continuous monitoring of cardiac status is recommended to identify any deterioration promptly (5.2).

For individuals with bronchospastic disease, the use of beta blockers is contraindicated due to the risk of bronchospasm. Healthcare professionals should consider alternative therapies for these patients (5.3).

Concomitant administration of beta blockers with glycosides, clonidine, diltiazem, or verapamil may heighten the risk of bradycardia. Close monitoring of heart rate and rhythm is advised when these medications are used together (5.4).

In patients diagnosed with pheochromocytoma, it is essential to initiate treatment with an alpha blocker prior to starting beta blocker therapy to prevent hypertensive crises (5.5).

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta blocker therapy should not be routinely withdrawn before surgery, as this may lead to adverse cardiovascular events (5.6, 6.1).

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 for patients at risk (5.7).

In cases of thyrotoxicosis, abrupt withdrawal of beta blockers can precipitate a thyroid storm, a life-threatening condition. Therefore, careful management and gradual tapering are essential in these patients (5.8).

For individuals with peripheral vascular disease, beta blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is advised to assess for any worsening of symptoms (5.9).

It is important to note that patients receiving beta blockers may be unresponsive to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should consider alternative dosing strategies or adjunctive therapies in these situations (5.10).

Side Effects

Most adverse reactions associated with TOPROL-XL are mild and transient. In clinical trials, the most common adverse reactions reported in patients included tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash, with an incidence greater than 2%. In the context of hypertension and angina, these reactions were predominantly mild.

In the MERIT-HF study, 10.3% of patients receiving TOPROL-XL discontinued treatment due to adverse reactions, compared to 12.2% of those on placebo. Notably, during post-operative evaluations, TOPROL-XL was linked to a higher incidence of specific adverse events, including bradycardia (6.6% vs. 2.4% in placebo), hypotension (15% vs. 9.7%), stroke (1.0% vs. 0.5%), and death (3.1% vs. 2.3%).

Post-marketing experience has revealed additional adverse reactions across various systems. Cardiovascular effects included cold extremities, arterial insufficiency (often of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory reactions encompassed wheezing (bronchospasm) and dyspnea. Central nervous system effects reported included confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia. Gastrointestinal reactions included nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting.

Hypersensitive reactions such as pruritus were noted, along with miscellaneous effects including musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Potentially serious adverse reactions have also been identified. Central nervous system effects may include reversible mental depression progressing to catatonia, characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic concerns include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. Hypersensitive reactions may manifest as laryngospasm and respiratory distress.

In cases of overdosage, patients may experience severe bradycardia, hypotension, and cardiogenic shock. Clinical presentations can also 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 pharmacological effects. Clinicians should monitor patients closely for signs of increased hypotension or bradycardia when these drug classes are used together.

Inhibition of the CYP2D6 enzyme can result in elevated concentrations of metoprolol. It is advisable to consider dosage adjustments of metoprolol in patients receiving strong CYP2D6 inhibitors to mitigate the risk of adverse effects associated with increased drug levels.

Beta-blockers, including metoprolol, have the potential to exacerbate rebound hypertension following the discontinuation of clonidine. Therefore, it is recommended that healthcare providers exercise caution and monitor blood pressure closely in patients transitioning off clonidine therapy while on beta-blockers.

Packaging & NDC

The table below lists all NDC Code configurations of Toprol (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 TOPROL-XL (0.2, 1, or 2 mg/kg once daily) for a duration of 4 weeks. The study did not achieve its primary endpoint of demonstrating a dose response for reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for 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 beats per minute, 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 TOPROL-XL have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies of TOPROL-XL 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 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 TOPROL-XL, 50% (990) of the participants were aged 65 years and older, and 12% (238) 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 elderly 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 geriatric patients.

Pregnancy

Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. 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 the use of metoprolol during pregnancy. However, 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. Conversely, 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.

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, necessitating careful monitoring and management of pregnant women with hypertension.

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. While data from published observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy, the inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality should be considered, as these studies have methodological limitations that hinder interpretation.

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, there is no information regarding the effects of metoprolol on milk production. Healthcare professionals should monitor the breastfed infant for bradycardia and other symptoms of beta-blockade, such as listlessness or hypoglycemia.

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 17.0 to 158.7 mcg), 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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 TOPROL-XL may present with a range of severe clinical manifestations. The most notable signs and symptoms 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 imperative to consider intensive care management for the patient. Those with underlying conditions such as myocardial infarction or heart failure are particularly susceptible to 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.

Management Strategies

• Bradycardia: The need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and associated conduction disorders.

• Hypotension: Management should focus on treating the underlying bradycardia. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be necessary to stabilize blood pressure.

• Heart Failure and 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 considered in cases of vasodilation.

• Bronchospasm: This condition can typically be reversed with the use of bronchodilators.

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned management strategies should be prioritized in the treatment of TOPROL-XL overdosage.

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 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

During post-approval use of TOPROL-XL or immediate-release metoprolol, various adverse reactions have been identified through voluntary reports and 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 reported include cold extremities, arterial insufficiency (typically of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory adverse reactions consist of wheezing (bronchospasm) and dyspnea.

Central nervous system effects encompass confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia. Gastrointestinal reactions include nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitivity reactions have been noted as pruritus.

Miscellaneous adverse events 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.

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

Patient Counseling

Patients should be advised to take TOPROL-XL 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 TOPROL-XL 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 TOPROL-XL has been determined. Patients should 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 TOPROL-XL.

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.

Parents or caregivers of patients should be informed about the risk of hypoglycemia when TOPROL-XL is administered to patients who are not feeding regularly or who are vomiting. They should also be instructed on how to recognize the signs of hypoglycemia and to monitor for any signs and symptoms of hypoglycemia in patients.

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 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) as outlined by the United States Pharmacopeia (USP) guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Post-marketing experience has revealed a range of potential adverse reactions associated with the medication. Cardiovascular effects may include cold extremities, arterial insufficiency (often of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory issues such as wheezing (bronchospasm) and dyspnea have also been reported.

Central nervous system effects can manifest as confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety or nervousness, hallucinations, and paresthesia. Gastrointestinal disturbances may include nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitive reactions such as pruritus have been noted, along with miscellaneous effects like musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Clinicians should be aware of the potential for reversible mental depression that can progress to catatonia, as well as 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. Other serious adverse reactions include agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura, laryngospasm, and respiratory distress.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Toprol as submitted by Aralez Pharmaceuticals US Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)