Toprol Xl

Description

TOPROL-XL, metoprolol succinate, is a beta-1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as 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). Metoprolol succinate, USP is a white crystalline powder with a molecular weight of 652.8. 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 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 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 mg or 25 mg, depending on the patient's condition and response.

When transitioning from immediate-release metoprolol to TOPROL-XL, it is essential to use 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 patients experiencing 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.

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

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 necessary to routinely withdraw chronic beta-blocker therapy before surgery, as this may lead to adverse cardiovascular events.

Patients receiving 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. Caution is advised when managing patients with this condition.

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 on beta-blockers may be unresponsive to the usual doses of epinephrine used for the treatment of allergic reactions. Healthcare professionals should consider alternative treatment strategies in these cases.

Side Effects

Most adverse reactions reported in clinical trials and post-marketing experiences have been mild and transient. The most common adverse reactions occurring in more than 2% of patients include tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.

In the MERIT-HF study, adverse reactions with an incidence of ≥ 1% in the TOPROL-XL group that were greater than placebo by more than 0.5% included dizziness/vertigo (1.8% in TOPROL-XL vs. 1.0% in placebo) and bradycardia (1.5% in TOPROL-XL vs. 0.4% in placebo). Additionally, in post-operative settings, the use of TOPROL-XL was associated with a higher incidence of bradycardia (6.6% vs. 2.4% in placebo), hypotension (15% vs. 9.7% in placebo), stroke (1.0% vs. 0.5% in placebo), and death (3.1% vs. 2.3% in placebo).

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

Hypersensitive reactions such as pruritus have also been noted. Miscellaneous adverse reactions include 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.

Potential adverse reactions of concern 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 neuropsychometrics. Hematologic concerns include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. Hypersensitive reactions may also manifest as laryngospasm and respiratory distress.

In cases of overdosage, patients may exhibit severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, nausea, and vomiting.

Neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression.

Drug Interactions

There are currently no documented drug interactions associated with 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 Toprol Xl (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) over a 4-week period. 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 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 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 compared to 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 and consideration of individual patient factors are 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 raises 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 the published literature has reported inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol, methodological limitations in these studies, such as retrospective design and concomitant use of other medications, hinder definitive conclusions about 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. However, it is recommended to 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. There is no information regarding the effects of metoprolol on milk production.

Renal Impairment

Patients with renal impairment do not exhibit clinically significant differences in the systemic availability and half-life of metoprolol compared to individuals with normal renal function. Consequently, no dosage reduction is necessary for patients with chronic renal failure. Monitoring of renal function may still be warranted as part of routine clinical practice, but adjustments to the metoprolol dosing regimen are not required in this population.

Hepatic Impairment

Patients with hepatic impairment may experience increased blood levels of metoprolol due to the drug's metabolism by the liver. As no studies have been conducted specifically in this population, it is recommended that therapy be initiated at lower doses than those typically recommended for the intended indication. Furthermore, doses should be increased gradually to monitor for any adverse effects and to ensure patient safety. Careful consideration and monitoring of liver function are advised when treating patients with compromised hepatic function.

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 cases of suspected overdosage, it is imperative to consider intensive care management. Patients with underlying conditions such as myocardial infarction or heart failure are particularly susceptible to significant hemodynamic instability, necessitating close monitoring and intervention.

Bradycardia resulting from overdose may require specific treatments. The administration of atropine, adrenergic-stimulating drugs, or the placement of a pacemaker should be evaluated based on the severity of the bradycardia and any associated conduction disorders.

For hypotension, it is essential to address the underlying bradycardia. Intravenous vasopressor infusion, utilizing agents such as dopamine or norepinephrine, may be warranted to stabilize blood pressure.

In instances of heart failure and shock, appropriate management may include volume expansion and the injection of glucagon. Additionally, intravenous administration of adrenergic drugs, such as dobutamine, may be beneficial, particularly when α1 receptor agonistic drugs are indicated in the presence of vasodilation.

Bronchospasm, a potential complication of overdose, can typically be reversed with the use of bronchodilators, providing symptomatic relief.

It is crucial for healthcare professionals to remain vigilant in recognizing these symptoms and implementing the recommended management strategies to mitigate the effects of TOPROL-XL 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. 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. 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 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 events consist of wheezing (bronchospasm) and dyspnea.

Central Nervous System reactions encompass confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia.

Gastrointestinal reactions reported include nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting.

Hypersensitive reactions have been noted as pruritus.

Miscellaneous events 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.

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 should 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. Patients or caregivers should also be informed about the risk of hypoglycemia when TOPROL-XL is 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 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

Postmarketing experience has revealed a range of adverse reactions associated with the medication. Cardiovascular effects 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 may manifest as confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety or nervousness, hallucinations, and paresthesia. Gastrointestinal disturbances include nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitive reactions such as pruritus, laryngospasm, and respiratory distress have been noted. Additional miscellaneous effects encompass 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 potential severe adverse reactions, including reversible mental depression that can progress to catatonia, characterized by disorientation, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic concerns include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Toprol Xl as submitted by Melinta Therapeutics, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)