Metoprolol tartrate/Hydrochlorothiazide

Description

Metoprolol tartrate and hydrochlorothiazide tablets, USP combine the antihypertensive effects of metoprolol tartrate, a beta adrenoreceptor blocker, and hydrochlorothiazide, a thiazide diuretic. These tablets are formulated for oral administration and are available in two strengths: the 50/25 tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP, while the 100/25 tablets contain 100 mg of metoprolol tartrate USP and 25 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 96% ethanol, slightly soluble in acetone, and insoluble in ether.

Hydrochlorothiazide USP 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.

The tablets also contain inactive ingredients, including colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, povidone, lactose monohydrate, and powdered cellulose.

Uses and Indications

Metoprolol tartrate and hydrochlorothiazide tablet is indicated for the treatment of hypertension, aimed at lowering blood pressure. Effective management of blood pressure 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 provider. 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. 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 risk of further cardiac conduction issues. Additionally, the product is contraindicated in patients with anuria, as renal function may be critically impaired.

Warnings and Precautions

Patients should be closely monitored for several critical conditions when using this medication. Abrupt cessation of therapy may exacerbate myocardial ischemia, necessitating careful consideration of treatment discontinuation. Additionally, the medication may worsen congestive heart failure, and patients with this condition should be monitored closely for any signs of deterioration.

In patients with a history of bronchospasm, the use of beta-blockers is contraindicated due to the potential for exacerbating respiratory symptoms. Bradycardia is another concern; healthcare professionals should assess heart rate regularly and be prepared to manage any significant reductions.

Prior to major surgical procedures, it is essential to avoid discontinuing therapy, as this may lead to adverse cardiovascular events. For patients with diabetes, the medication may mask symptoms of hypoglycemia and alter glucose levels; therefore, regular monitoring of blood glucose is recommended to prevent complications.

Routine laboratory tests should include periodic monitoring of serum electrolytes and creatinine to assess renal function and electrolyte balance. In patients with peripheral vascular disease, the medication may aggravate symptoms of arterial insufficiency, warranting careful evaluation of vascular status.

For individuals diagnosed with pheochromocytoma, it is crucial to initiate therapy with an alpha blocker before considering the use of this medication. Abrupt withdrawal in patients with thyrotoxicosis can precipitate a thyroid storm, a life-threatening condition that requires immediate medical attention.

Finally, it is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions, necessitating alternative treatment strategies in such cases.

Side Effects

Patients receiving treatment with metoprolol tartrate and hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions include the potential for abrupt cessation of therapy to exacerbate myocardial ischemia and worsen congestive heart failure. Patients with bronchospasm should avoid beta-blockers, and bradycardia may occur. It is critical to avoid discontinuing therapy prior to major surgery, as this may lead to complications. Additionally, patients with diabetes should be monitored closely, as the medication may mask symptoms of hypoglycemia and alter glucose levels. Regular monitoring of serum electrolytes and creatinine is recommended, particularly in patients with peripheral vascular disease, as the medication can aggravate symptoms of arterial insufficiency. In cases of pheochromocytoma, therapy should first be initiated with an alpha blocker. Abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, and 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 bradycardia, hypotension, and cardiac conduction disturbances. Overdosage of beta-adrenergic blockers may lead to bradyarrhythmia, heart failure, bronchospasm, atrioventricular block, hypoxia, and impairment of consciousness or coma. Symptoms of thiazide diuretic overdose are rare but may include acute loss of fluid, electrolytes, and magnesium, leading to hypotension, dizziness, muscle cramps, and renal impairment or failure. Altered laboratory findings such as hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased BUN may also occur.

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

Safety and effectiveness in pediatric patients have not been established, and clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other clinical experiences have not identified significant differences in responses between elderly and younger patients. Given that hydrochlorothiazide is substantially excreted by the kidney, the risk of toxic reactions may be greater in patients with impaired renal function.

Drug Interactions

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

Inhibitors of CYP2D6 can result in increased concentrations of metoprolol, necessitating careful monitoring of the patient for potential adverse effects. Dose adjustments may be required based on clinical response.

The concomitant use of digitalis glycosides, clonidine, diltiazem, and verapamil may also lead to bradycardia. Clinicians should monitor heart rate closely and consider dose modifications of these agents if bradycardia occurs.

Withdrawal of clonidine can precipitate rebound hypertension, which should be managed appropriately to prevent complications.

Antidiabetic medications may require dosage adjustments when used in conjunction with other therapies, 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 therapeutic effects. It is advisable to separate the administration of these agents to mitigate this interaction.

The use of lithium alongside other medications poses a risk of lithium toxicity. Monitoring of serum lithium levels is essential to avoid 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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider this lack of established safety and efficacy when making treatment decisions for pediatric patients.

Geriatric Use

Elderly patients may not respond differently to metoprolol tartrate and hydrochlorothiazide tablets compared to younger patients, as clinical studies did not include a sufficient number of subjects aged 65 and over to draw definitive conclusions. However, other clinical experiences have not identified significant differences in responses between these age groups.

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. Monitoring of renal function may be beneficial in this population.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start 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 basis. 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 doses up to 3000 and 1000 mg/kg/day, respectively, produced no harm to the fetus, although thiazides cross the placental barrier and appear in cord blood.

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, as well as the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that neonates be observed for these symptoms and managed appropriately. 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, the findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol have methodological limitations that hinder interpretation.

Lactation

The combination of metoprolol tartrate/hydrochlorothiazide has been shown to affect lactation in animal studies. In rats, administration of this combination from mid-late gestation through lactation resulted in increased post-implantation loss and decreased neonatal survival.

Metoprolol is known to cross the placenta, and neonates born to lactating mothers receiving metoprolol may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that healthcare professionals observe breastfed infants for these symptoms and manage them accordingly.

Hydrochlorothiazide also crosses the placental barrier and can be detected in cord blood, indicating potential exposure to breastfed infants. Caution is advised when prescribing this combination to lactating mothers, and careful monitoring of the nursing infant is warranted.

Renal Impairment

Patients with renal impairment should have their serum electrolytes and creatinine monitored periodically. Dosing adjustments may be necessary based on the degree of reduced kidney function to ensure safety and efficacy. Healthcare professionals are advised to assess renal function regularly to guide treatment decisions and minimize the risk of adverse effects.

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, the clinical manifestations can vary significantly depending on the specific medication involved.

Beta Adrenergic Blockers

The most frequently observed signs associated with the overdosage of beta adrenergic blockers include bradycardia and bradyarrhythmia, hypotension, heart failure, and cardiac conduction disturbances. Additional symptoms may encompass bronchospasm, atrioventricular block, hypoxia, and impairment of consciousness, which can progress to coma. Severe cases may lead to cardiogenic shock, accompanied by gastrointestinal symptoms such as nausea and vomiting.

Thiazide Diuretics

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

Laboratory Findings

Altered laboratory findings are also common in cases of overdosage. These may include hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, and metabolic alkalosis, as well as increased blood urea nitrogen (BUN) levels.

Recommended Actions

Healthcare professionals should monitor patients closely for these symptoms and laboratory changes. Management of overdosage should be supportive and symptomatic, with particular attention to cardiovascular stability and electrolyte balance. In severe cases, advanced interventions may be necessary to address life-threatening complications.

Nonclinical Toxicology

No specific teratogenic effects have been identified for metoprolol tartrate and hydrochlorothiazide tablets. Studies indicate that these tablets do not impair fertility in male or female rats when administered gavaged doses up to 200/50 mg/kg. Additionally, no evidence of impaired fertility due to metoprolol tartrate was observed in rats at doses up to 22 times the daily dose of 200 mg for a 60 kg patient. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 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 two-year study involving rats, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histological changes observed that appeared to be drug-related included 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, benign lung tumors were more frequently observed in female mice receiving the highest dose compared to untreated control animals; however, there was no increase in malignant or total (benign plus malignant) lung tumors. This study was repeated in CD-1 mice, where no statistically or biologically significant differences were noted between treated and control mice of either sex for any type of tumor. All mutagenicity tests conducted were negative.

Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats. There was equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not found to be genotoxic in the Ames bacterial mutagenicity test or the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. However, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange, the Mouse Lymphoma Cell assays, and the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Postmarketing Experience

Postmarketing experience has identified a risk of hypoglycemia associated with the administration of Metoprolol tartrate and hydrochlorothiazide tablets in patients who are fasting or experiencing vomiting. This information is derived from voluntary reports and surveillance programs, highlighting the importance of monitoring blood glucose levels in these specific patient populations.

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 situations where patients are fasting or experiencing vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia, as detailed in the Warnings and Precautions section.

Patients should be advised to take metoprolol tartrate and hydrochlorothiazide tablets as directed, ideally 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 of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 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 on the necessity of not interrupting therapy without consulting their physician. In cases 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 Ajanta Pharma USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)