Kapspargo

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 designed 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 that continuously releases metoprolol 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 relevant 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

KAPSPARGO Sprinkle is indicated for the treatment of hypertension, with the primary goal of lowering blood pressure. Effective blood pressure reduction is associated with a decreased risk of both fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.

Additionally, KAPSPARGO Sprinkle is indicated for the management of angina pectoris. It is also indicated for patients with heart failure, where it serves to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with KAPSPARGO Sprinkle.

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 once daily. This dosage may be doubled every two weeks, up to the highest dose tolerated by the patient or a maximum of 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, 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, 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.

Heart Failure Patients with pre-existing heart failure may experience worsening cardiac function. Continuous monitoring of cardiac status is recommended for these individuals to ensure timely intervention if deterioration occurs.

Bronchospastic Disease In patients with bronchospastic diseases, the use of beta blockers is contraindicated due to the potential for exacerbating respiratory symptoms. Alternative therapies should be considered for these patients.

Concomitant Medications The concomitant use of beta blockers with glycosides, clonidine, diltiazem, or verapamil may increase the risk of bradycardia. Healthcare professionals should monitor heart rate and rhythm closely in patients receiving these combinations.

Pheochromocytoma For patients diagnosed with pheochromocytoma, it is essential to initiate therapy with an alpha blocker prior to the introduction of beta blockers to prevent hypertensive crises.

Major Surgery In the context of major non-cardiac surgery, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta-blocker therapy should not be routinely withdrawn prior to surgical procedures, as this may lead to adverse cardiovascular events.

Hypoglycemia Beta blockers may increase the risk of hypoglycemia and can mask the early warning signs of this condition. Patients with diabetes should be monitored closely for signs of low blood sugar, particularly when initiating or adjusting beta blocker therapy.

Thyrotoxicosis Abrupt withdrawal of beta blockers in patients with thyrotoxicosis can precipitate a thyroid storm, a life-threatening condition. Gradual tapering is advised in these cases to prevent such complications.

Peripheral Vascular Disease Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency when treated with beta blockers. Careful assessment and monitoring of vascular status are recommended.

Allergic Reactions Patients on beta blockers may exhibit reduced responsiveness to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative treatment strategies in such scenarios.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by seriousness and frequency.

Most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash. These reactions are generally mild to moderate in severity.

Serious adverse reactions may occur, including worsening heart failure and exacerbation of myocardial ischemia, particularly with abrupt cessation of therapy. Patients with bronchospastic disease should avoid beta blockers due to the risk of bronchospasm. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta blockers can increase the risk of bradycardia. In patients with pheochromocytoma, therapy should be initiated with an alpha blocker to prevent complications.

Patients undergoing major surgery should avoid the initiation of high-dose extended-release metoprolol and should not routinely withdraw chronic beta-blocker therapy prior to surgery. Additionally, there is a risk of hypoglycemia, which may mask early warning signs, and abrupt withdrawal in patients with thyrotoxicosis could precipitate a thyroid storm. Peripheral vascular disease may be aggravated, leading to worsened symptoms of arterial insufficiency. It is also important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Known hypersensitivity reactions include 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, nausea, and vomiting.

Drug Interactions

Catecholamine-depleting drugs, when administered concurrently with beta-blocking agents, may produce an additive effect. This interaction necessitates careful monitoring of blood pressure and heart rate, as the combined effects could lead to significant cardiovascular changes.

Inhibitors of the CYP2D6 enzyme are known to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol in patients receiving CYP2D6 inhibitors to avoid potential adverse effects associated with elevated drug levels.

Additionally, beta-blockers, including metoprolol, may worsen rebound hypertension following the discontinuation of clonidine. It is advisable to monitor blood pressure closely in patients transitioning off clonidine, particularly if they are also receiving beta-blocker therapy, to manage any potential hypertensive episodes effectively.

Packaging & NDC

The table below lists all NDC Code configurations of Kapspargo (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) over a 4-week period. The study did not achieve its primary endpoint of demonstrating a dose response for the reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for the 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 metoprolol succinate have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies evaluating metoprolol succinate for hypertension did not include a sufficient number of subjects aged 65 and older to ascertain whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not revealed significant differences in responses between elderly and younger populations.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to metoprolol succinate, 50% (990 patients) were aged 65 years and older, and 12% (238 patients) were aged 75 years and older. The findings indicated no notable differences in efficacy or the incidence of adverse reactions between older and younger patients.

Given the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, it is advisable to initiate treatment with a low starting dose in geriatric patients. Careful monitoring is recommended to ensure safety and efficacy in this population.

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 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, during pregnancy.

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 increases 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, methodological limitations in these studies, such as retrospective design and concomitant use of other medications, hinder definitive conclusions regarding 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, 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) taking metoprolol of unspecified amount, 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 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 dosage are not required based on renal status.

Hepatic Impairment

Patients with hepatic impairment may experience increased blood levels of metoprolol succinate due to its hepatic metabolism. No studies have been conducted to specifically evaluate the pharmacokinetics of metoprolol succinate in this population. Consequently, it is recommended that therapy be initiated at lower doses than those typically recommended for the specific indication. Doses should be increased gradually, taking into account the patient's liver function and response to treatment. Close monitoring of the patient's clinical status and any potential adverse effects is advised to ensure safe and effective use of metoprolol succinate in individuals with compromised liver function.

Overdosage

Overdosage of metoprolol succinate can result in a range of severe clinical manifestations that require immediate medical attention.

Signs and Symptoms

The clinical presentation of metoprolol succinate overdosage may include severe bradycardia, hypotension, and cardiogenic shock. Additional symptoms can manifest as atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal disturbances such as nausea and vomiting.

Treatment

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. It is important to note that beta-blocker overdose may lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Specific 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 the presence 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. Prompt recognition and management of these symptoms are crucial for 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 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

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 should be advised to take KAPSPARGO Sprinkle 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 KAPSPARGO Sprinkle 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 KAPSPARGO Sprinkle 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 KAPSPARGO Sprinkle.

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 KAPSPARGO Sprinkle 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 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

Patients should be advised to seek emergency treatment in the event of severe hypoglycemia. Additionally, it is important to warn patients against interrupting therapy without consulting their physician first.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Kapspargo as submitted by Sun Pharmaceutical Industries, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)