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: 50/25 tablets contain 50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; 100/25 tablets contain 100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; and 100/50 tablets contain 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide.

Metoprolol tartrate is chemically defined as (±)-1-(Isopropylamino)-3-p-(2-methoxyethyl)phenoxy-2-propanol L-(+)-tartrate (2:1) salt, with a molecular weight of 684.81. 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 identified as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.74. It is a white or practically white, practically odorless, crystalline powder that 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 several inactive ingredients, including anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch (corn), and sodium lauryl sulfate.

Uses and Indications

Metoprolol tartrate and hydrochlorothiazide 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, particularly 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 are contraindicated from use 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

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 introducing this medication to prevent hypertensive crises. Furthermore, abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, a life-threatening condition that requires immediate medical attention.

Lastly, 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 may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions include the potential for exacerbation of myocardial ischemia upon abrupt cessation of therapy, worsening of congestive heart failure, and the risk of bronchospasm, particularly in patients with a history of respiratory conditions. Bradycardia is also a notable serious reaction, necessitating careful monitoring. Patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated. In cases of thyrotoxicosis, abrupt withdrawal of metoprolol could precipitate a thyroid storm. Additionally, patients with pheochromocytoma should first initiate therapy with an alpha blocker to avoid complications. It is important to note that patients may be unresponsive to standard doses of epinephrine used for treating allergic reactions.

Common adverse reactions observed in clinical trials and postmarketing experiences include the need for monitoring of serum electrolytes and creatinine levels periodically, as well as the potential for diabetes patients to experience masked symptoms of hypoglycemia and altered glucose levels. Patients are advised to monitor their glucose levels closely.

Contraindications for metoprolol include hypersensitivity to metoprolol tartrate, hydrochlorothiazide, or other sulfonamide-derived drugs, as well as conditions such as cardiogenic shock, decompensated heart failure, sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place. Anuria is also a contraindication for the use of this medication.

In cases of overdosage, the most frequently observed signs include bradycardia, bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, and impairment of consciousness or coma. Cardiogenic shock, nausea, and vomiting may also occur. With thiazide diuretics, acute intoxication is rare, but may lead to significant fluid and electrolyte loss, with symptoms such as hypotension, dizziness, muscle cramps, renal impairment, and altered consciousness. Laboratory findings may reveal hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased BUN.

Fetal and neonatal adverse reactions are also a concern, as metoprolol crosses the placenta. Neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is essential to observe these neonates for any symptoms of these conditions and manage them accordingly.

Drug Interactions

Catecholamine-depleting drugs, such as monoamine oxidase (MAO) inhibitors, may lead to significant cardiovascular effects, including hypotension and bradycardia when co-administered.

Pharmacokinetic interactions are observed with CYP2D6 inhibitors, which can result in increased concentrations of metoprolol, necessitating careful monitoring of blood pressure and heart rate.

The concomitant use of digitalis glycosides, clonidine, diltiazem, and verapamil may also induce bradycardia. Special attention should be given to patients receiving clonidine, as withdrawal can precipitate rebound hypertension.

Antidiabetic medications may require dosage adjustments when used in conjunction with this drug, highlighting the need for close monitoring of blood glucose levels.

Cholestyramine and colestipol can impair the absorption of thiazide diuretics, potentially diminishing their therapeutic effects.

The use of lithium alongside this drug poses a risk of lithium toxicity, warranting regular monitoring of lithium levels.

Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics, which should be considered when prescribing these agents together.

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, and healthcare professionals are advised to consider the lack of data when prescribing to this population.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were not adequately represented in clinical studies of metoprolol tartrate and hydrochlorothiazide tablets, making it difficult to ascertain whether they respond differently compared to younger patients. However, available clinical experience has not indicated any significant differences in responses between elderly and younger patients.

It is important to note that hydrochlorothiazide is primarily excreted by the kidneys, which raises concerns regarding the potential for 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 risks.

In general, when prescribing for elderly patients, it is advisable to adopt a cautious approach to dose selection, typically initiating treatment at the lower end of the dosing range. This recommendation is based on the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect drug metabolism and excretion.

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-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.

Neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Therefore, it is recommended that healthcare professionals observe neonates for these symptoms and manage them 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 post-partum hemorrhage. Additionally, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. 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, the findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol have methodological limitations that hinder interpretation.

Lactation

There are no data on the presence of metoprolol tartrate and hydrochlorothiazide in human milk, the effects on the breastfed infant, or the effects on milk production. However, available data from published literature indicate that both metoprolol and hydrochlorothiazide are present in human milk.

Reports suggest that there are no adverse effects on breastfed infants exposed to metoprolol or hydrochlorothiazide during lactation. It is important to note that 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. The estimated daily infant dose of metoprolol received from breastmilk has been reported to range 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, the average amount of metoprolol 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 and her infant showed a peak concentration of 275 mcg/L in breast milk at 3 hours following a 50 mg dose, with no drug detected in the infant’s plasma (< 20 mcg/L) at 2 and 11 hours post-dose.

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

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 renal function decline, and healthcare professionals should exercise caution when prescribing to this population to ensure safety and efficacy.

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

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. Additional serious manifestations may involve atrioventricular block, hypoxia, impairment of consciousness or coma, and cardiogenic shock. Patients may also experience gastrointestinal symptoms such as nausea and vomiting.

Management of beta-adrenergic blocker overdosage should focus on supportive care and symptomatic treatment. Continuous monitoring of cardiac function and vital signs is essential. In cases of severe bradycardia or hypotension, the administration of atropine or intravenous fluids may be indicated. In more critical situations, the use of glucagon or pacing may be necessary to stabilize the patient.

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 overdose may include hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness. Healthcare professionals should be aware of altered laboratory findings that can accompany thiazide overdose, such as hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN) levels.

Management of thiazide diuretic overdosage should involve the restoration of fluid and electrolyte balance. This may include the administration of intravenous fluids and electrolytes as needed, along with close monitoring of renal function and laboratory parameters.

Nonclinical Toxicology

No evidence of impaired fertility was observed in male or female rats administered gavaged doses of metoprolol tartrate up to 200/50 mg/kg prior to mating and throughout gestation and rearing of young. Similarly, a study in rats indicated no impairment of fertility at doses up to 22 times the daily dose of 200 mg in a 60 kg patient. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex when exposed to doses of up to 100 and 4 mg/kg/day prior to mating and throughout gestation.

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate and hydrochlorothiazide. In a 2-year study in rats at 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 related to the drug were a 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 oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) 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, which showed no statistically or biologically significant differences between treated and control mice for any type of tumor.

Carcinogenicity and mutagenicity studies have not been conducted specifically with metoprolol tartrate and hydrochlorothiazide tablets. 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, although equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity test or the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. However, positive test results were obtained 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. All mutagenicity tests performed were negative.

Postmarketing Experience

No specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 outlined 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 includes a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, the product must be protected from moisture to ensure its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)