Metoprolol tartrate/Hydrochlorothiazide

Description

Metoprolol tartrate and hydrochlorothiazide tablets, USP combine the antihypertensive properties of metoprolol tartrate, a beta adrenoreceptor blocker, and hydrochlorothiazide, a thiazide diuretic. These tablets are formulated for oral administration and are available in three strengths: 50 mg/25 mg, 100 mg/25 mg, and 100 mg/50 mg.

The 50 mg/25 mg tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP. The 100 mg/25 mg tablets consist of 100 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP, while the 100 mg/50 mg tablets contain 100 mg of metoprolol tartrate USP and 50 mg of hydrochlorothiazide USP.

Metoprolol tartrate USP is characterized as (±)-1-(Isopropylamino)-3-p-(2-methoxyethyl)phenoxy-2-propanol L-(+)-tartrate (2:1) salt, with a molecular weight of 684.82. It appears as a white, crystalline powder that is very soluble in water, freely soluble in methylene chloride, chloroform, and alcohol, slightly soluble in acetone, and insoluble in ether.

Hydrochlorothiazide is defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.73. This compound is a white or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, chloroform, and dilute mineral acids.

Inactive ingredients in the formulation include microcrystalline cellulose, anhydrous lactose, lactose monohydrate, pregelatinized starch, corn starch, compressible sugar, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, D&C Yellow No. 10 (in the 50 mg/25 mg and 100 mg/50 mg tablets), and FD&C Red No. 40 and FD&C Yellow No. 6 (in the 100 mg/25 mg tablets).

Uses and Indications

Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Effective management of hypertension is associated with a reduction in the risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

There are no teratogenic effects associated with this medication. Additionally, no nonteratogenic effects have been reported.

Dosage and Administration

The usual dose of Hydrochlorothiazide is 12.5 mg to 25 mg, administered once daily. Metoprolol tartrate is typically prescribed at a dose of 100 mg, also given once daily.

Both medications should be taken orally, with or without food, as directed by the healthcare professional. It is important to monitor the patient's response to therapy and adjust the dosage as necessary to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to metoprolol tartrate, hydrochlorothiazide, or other sulfonamide-derived drugs due to the risk of severe allergic reactions.

It is also contraindicated in individuals experiencing cardiogenic shock or decompensated heart failure, as these conditions may be exacerbated by the pharmacological effects of the medication.

Patients with sinus bradycardia, sick sinus syndrome, or greater than first-degree atrioventricular block should not use this product unless a permanent pacemaker is in place, due to the potential for significant cardiac complications.

Additionally, the product is contraindicated in patients with anuria, as renal function may be adversely affected.

Warnings and Precautions

Abrupt cessation of therapy may lead to exacerbation of myocardial ischemia; therefore, it is crucial to taper off the medication under medical supervision. In patients with congestive heart failure, the use of this medication may worsen their condition, necessitating careful monitoring and potential adjustment of therapy.

Healthcare professionals should be vigilant for bronchospasm, particularly in patients with a history of respiratory conditions, as beta-blockers are contraindicated in such cases. Bradycardia is another potential side effect that requires monitoring, especially in patients with pre-existing heart conditions.

Prior to any major surgical procedures, it is advised to avoid discontinuing therapy, as this may lead to adverse cardiovascular events. In diabetic patients, this medication may mask the symptoms of hypoglycemia and alter glucose levels; therefore, regular monitoring of blood glucose is recommended to ensure patient safety.

Periodic assessment of serum electrolytes and creatinine levels is essential to detect any potential imbalances or renal impairment during treatment. For patients with peripheral vascular disease, this medication may aggravate symptoms of arterial insufficiency, warranting close observation.

In cases of pheochromocytoma, it is imperative to initiate therapy with an alpha blocker before introducing this medication to prevent hypertensive crises. Additionally, abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, which is a medical emergency.

Finally, it is important to note that patients may exhibit unresponsiveness to the standard doses of epinephrine used for treating allergic reactions, necessitating careful consideration of dosing and alternative treatment strategies in such scenarios.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, which can be categorized by seriousness and frequency.

Serious adverse reactions include the potential for exacerbation of myocardial ischemia upon abrupt cessation of therapy, as well as worsening of congestive heart failure. Patients with bronchospasm should avoid beta-blockers, and those with peripheral vascular disease may find their symptoms of arterial insufficiency aggravated. Bradycardia is another serious concern, and patients with pheochromocytoma should first initiate therapy with an alpha blocker. Additionally, abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Common adverse reactions observed in clinical trials and postmarketing experiences include hypotension, dizziness, and muscle cramps. Patients may also experience renal impairment or failure, sedation, and impairment of consciousness. Monitoring of serum electrolytes and creatinine is recommended periodically, as altered laboratory findings such as hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased BUN may occur.

In cases of overdosage, the most frequently observed signs include bradycardia and bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, and even impairment of consciousness or coma. Cardiogenic shock, nausea, and vomiting may also be present. With thiazide diuretics, acute intoxication is rare, but may lead to acute loss of fluid, electrolytes, and magnesium, with symptoms similar to those of beta-adrenergic blocker overdose.

Fetal and neonatal adverse reactions have been noted in neonates born to mothers receiving metoprolol during pregnancy. These neonates may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is advised to observe these neonates for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and to manage them accordingly.

Patients should be counseled on the importance of not discontinuing therapy prior to major surgery and the need for careful monitoring of glucose levels, particularly in those with diabetes, as the medication may mask symptoms of hypoglycemia and alter glucose levels.

Drug Interactions

Catecholamine-depleting drugs, such as monoamine oxidase (MAO) inhibitors, may lead to significant cardiovascular effects, including hypotension and bradycardia. Monitoring of blood pressure and heart rate is advised when these agents are co-administered.

CYP2D6 inhibitors can increase the concentration of metoprolol, necessitating careful monitoring of therapeutic effects and potential side effects. Dose adjustments may be required based on clinical response.

The concomitant use of digitalis glycosides, clonidine, diltiazem, and verapamil may result in bradycardia. Patients should be monitored for heart rate and rhythm, and dosage adjustments may be necessary to mitigate this risk.

Clonidine withdrawal can lead to rebound hypertension. It is recommended that clinicians taper clonidine gradually to avoid this adverse effect.

Antidiabetic drugs may require dosage adjustments when used in conjunction with other medications, as their efficacy can be altered. Regular monitoring of blood glucose levels is recommended to ensure optimal control.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics, potentially diminishing their effectiveness. It is advisable to separate the administration of these agents to enhance therapeutic outcomes.

The use of lithium alongside other medications poses a risk of lithium toxicity. Regular monitoring of lithium levels is essential to prevent adverse effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. Clinicians should consider alternative pain management strategies or monitor blood pressure and fluid status closely when these agents are used concurrently.

Packaging & NDC

The table below lists all NDC Code configurations of Metoprolol Tartrate and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Clinical studies of metoprolol tartrate and hydrochlorothiazide tablets did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently compared to younger subjects. However, other reported clinical experiences have not identified significant differences in responses between geriatric patients and their younger counterparts.

It is important to note that hydrochlorothiazide is substantially excreted by the kidneys, which raises concerns regarding the risk of toxic reactions in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection in this population. Monitoring of renal function may be beneficial to mitigate potential risks.

In general, dose selection for elderly patients should be approached with caution. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Pregnancy

Untreated hypertension 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 of 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 up to 24 times the daily dose of 200 mg in a 60-kg patient, based on a mg/m² comparison. The combination of metoprolol tartrate and hydrochlorothiazide administered to rats from mid to late gestation through lactation also resulted in increased post-implantation loss and decreased neonatal survival. Hydrochlorothiazide, when administered to pregnant mice and rats during organogenesis at high doses, produced no harm to the fetus, although thiazides cross the placental barrier and appear in cord blood.

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 neonates be observed for these symptoms and managed accordingly.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and postpartum hemorrhage. It also increases the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

Data from published observational studies did not demonstrate an association of major congenital malformations with the use of either metoprolol or hydrochlorothiazide during pregnancy. However, methodological limitations in these studies, including retrospective design and concomitant use of other medications, hinder the interpretation of findings related to intrauterine growth retardation, preterm birth, and perinatal mortality. These studies cannot definitively establish or exclude any drug-associated risk during pregnancy.

Lactation

There are no data on the presence of metoprolol tartrate and hydrochlorothiazide in human milk, nor on the effects on the breastfed infant or milk production. However, available literature indicates that both metoprolol and hydrochlorothiazide are present in human milk. Reports suggest that there are no adverse effects on breastfed infants exposed to these medications during lactation.

Doses of hydrochlorothiazide associated with clinically significant diuresis may impair milk production, while there is no information regarding the effects of metoprolol on milk production. Lactating mothers should monitor breastfed infants for signs of drowsiness, poor feeding, bradycardia, or somnolence.

Based on published case reports, the estimated daily infant dose of metoprolol received from breastmilk ranges from 0.05 mg to less than 1 mg, with a relative infant dosage of 0.5% to 2% of the mother’s weight-adjusted dosage. In a small study involving three mothers taking unspecified amounts of metoprolol, the average amount present in breast milk was 71.5 mcg/day (range 17.0 to 158.7), corresponding to an average relative infant dosage of 0.5% of the mother’s weight-adjusted dosage.

A single study involving one woman taking a 50 mg dose of hydrochlorothiazide showed a peak concentration of 275 mcg/L in breast milk at 3 hours post-dose, with no detectable drug in the infant’s plasma at 2 hours and 11 hours following the mother’s dose.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for metoprolol tartrate and hydrochlorothiazide, as well as any potential adverse effects on the breastfed child from these medications or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment should be monitored for serum electrolytes and creatinine periodically. Dosing adjustments may be necessary based on the degree of reduced kidney function to ensure safety and efficacy. It is essential for healthcare professionals to assess renal function regularly and make appropriate modifications to the treatment regimen as needed.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage with beta-adrenergic blockers, healthcare professionals should be vigilant for a range of potential symptoms. The most frequently observed signs include bradycardia and bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, and bronchospasm. Additionally, patients may present with atrioventricular block, hypoxia, impairment of consciousness or coma, cardiogenic shock, as well as gastrointestinal symptoms such as nausea and vomiting.

Management of beta-adrenergic blocker overdosage typically involves supportive care and monitoring of vital signs. In severe cases, the use of atropine may be indicated to counteract bradycardia, while intravenous fluids and vasopressors may be necessary to address hypotension. Continuous cardiac monitoring is essential to detect any conduction disturbances.

For thiazide diuretics, acute intoxication is relatively rare; however, when it occurs, the most prominent feature is an acute loss of fluid, electrolytes, and magnesium. Symptoms of thiazide overdose may include hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness.

Altered laboratory findings are also common in cases of thiazide overdose, which may include hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN) levels. Management should focus on restoring fluid and electrolyte balance, and monitoring renal function closely.

In both scenarios, prompt recognition and appropriate management are critical to mitigate the effects of overdosage and prevent serious complications.

Nonclinical Toxicology

No teratogenic effects have been observed with metoprolol tartrate and hydrochlorothiazide tablets. Studies conducted in male and female rats administered gavaged doses of up to 200/50 mg/kg demonstrated no evidence of impaired fertility. Additionally, metoprolol tartrate did not impair fertility in rats at doses up to 22 times the daily dose of 200 mg in a 60 kg patient. Hydrochlorothiazide also showed no adverse effects on fertility in mice and rats of either sex when exposed to doses of up to 100 mg/kg/day and 4 mg/kg/day prior to mating and throughout gestation.

Carcinogenicity and mutagenicity studies have not been conducted specifically with metoprolol tartrate and hydrochlorothiazide tablets. However, long-term studies in animals have been performed to evaluate the carcinogenic potential. In a 2-year study involving rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms. The only histologic changes noted were a mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia.

In a separate 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors were observed more frequently in female mice receiving the highest dose compared to untreated controls. However, there was no increase in malignant or total lung tumors, nor in the overall incidence of tumors. This study was repeated in CD-1 mice, where no statistically or biologically significant differences were found between treated and control mice of either sex for any tumor type.

Regarding mutagenicity, all tests performed yielded negative results. Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. Nonetheless, there was equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity test or the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Furthermore, it was not genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were observed in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, as well as in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Postmarketing Experience

Patients and caregivers are advised of the risk of hypoglycemia associated with the use of metoprolol tartrate and hydrochlorothiazide tablets, particularly in individuals who are fasting or experiencing vomiting. It is important to instruct patients and caregivers on how to monitor for signs of hypoglycemia to ensure timely recognition and management of this potential adverse event. For further details, please refer to the Warnings and Precautions section (5.6).

Patient Counseling

Healthcare providers should inform patients or caregivers about the risk of hypoglycemia associated with the use of metoprolol tartrate and hydrochlorothiazide tablets, particularly in patients who are fasting or experiencing vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia, as outlined in the Warnings and Precautions section.

Patients should be advised to take metoprolol tartrate and hydrochlorothiazide tablets as directed, preferably with or immediately following meals, to optimize absorption and minimize potential side effects. In the event that a dose is missed, patients should be instructed to take only the next scheduled dose and to avoid doubling up on doses.

Additionally, patients must be cautioned against discontinuing metoprolol tartrate and hydrochlorothiazide tablets without first consulting their healthcare provider, as abrupt cessation may lead to adverse effects.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) as outlined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from moisture to maintain its integrity.

Additional Clinical Information

Clinicians are advised to monitor serum electrolytes and calcium levels periodically in patients undergoing treatment. It is important to counsel patients not to interrupt therapy without consulting their physician. In the event of severe hypoglycemia, patients should be instructed to seek emergency medical treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)