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 three strengths: 50/25, 100/25, and 100/50, containing 50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide, 100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide, and 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide, respectively.

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 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 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 inactive ingredients, including colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, povidone, lactose, and pregelatinized starch.

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 or nonteratogenic effects associated with this medication.

Dosage and Administration

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

Both medications should be taken orally, with or without food, as directed by the prescribing 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 the following situations:

Patients with hypersensitivity to metoprolol tartrate, hydrochlorothiazide, or other sulfonamide-derived drugs should not use this product due to the risk of severe allergic reactions.

The product is contraindicated in individuals experiencing cardiogenic shock or decompensated heart failure, as it may exacerbate these conditions.

Patients with sinus bradycardia, sick sinus syndrome, or greater than first-degree atrioventricular block are also contraindicated unless a permanent pacemaker is in place, due to the potential for significant cardiac complications.

Anuria is another contraindication, as the use of this product may lead to further renal impairment.

Warnings and Precautions

Abrupt cessation of therapy may lead to exacerbation of myocardial ischemia; therefore, healthcare professionals should exercise caution when discontinuing treatment. In patients with congestive heart failure, the medication may worsen symptoms, necessitating careful monitoring of cardiac status.

Bronchospasm is a potential risk, particularly in patients with a history of respiratory conditions. It is advised to avoid the use of beta-blockers in these individuals. Additionally, bradycardia may occur, and monitoring of heart rate is recommended to manage this risk effectively.

Prior to major surgical procedures, it is crucial not to discontinue therapy, as this may lead to adverse cardiovascular events. In diabetic patients, the medication may mask symptoms of hypoglycemia and alter glucose levels; therefore, regular monitoring of blood glucose is essential.

Periodic assessment of serum electrolytes and creatinine levels is recommended to ensure renal function and electrolyte balance are maintained. For patients with peripheral vascular disease, the 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 considering the use of this medication. Abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, which can be life-threatening.

Lastly, 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 in these scenarios.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication. Serious adverse reactions include the potential for unresponsiveness to the usual doses of epinephrine used to treat allergic reactions, which is highlighted in the boxed warning.

Warnings indicate that abrupt cessation of therapy may exacerbate myocardial ischemia and worsen congestive heart failure. Patients with bronchospasm should avoid beta-blockers, and bradycardia may occur. It is advised to avoid discontinuing therapy prior to major surgery. 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 for those with peripheral vascular disease, as the medication can aggravate symptoms of arterial insufficiency. In patients with pheochromocytoma, therapy should first be initiated with an alpha blocker. Abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm.

Contraindications 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.

In cases of overdosage, the most frequently observed signs associated with beta-adrenergic blocker overdose include bradycardia and bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, impairment of consciousness or coma, cardiogenic shock, and gastrointestinal symptoms such as nausea and vomiting.

For thiazide diuretics, acute intoxication is rare; however, the most prominent feature of overdose is acute loss of fluid, electrolytes, and magnesium. Symptoms may include hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness. Altered laboratory findings can also occur, including hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN) 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 patients be monitored closely during the discontinuation of clonidine therapy to manage potential increases in blood pressure.

Antidiabetic drugs may require dosage adjustments when used in conjunction with other medications. Regular monitoring of blood glucose levels is recommended to ensure optimal glycemic control.

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

The use of lithium alongside other medications poses a risk of lithium toxicity. Patients should be monitored for signs of toxicity, and serum lithium levels should be checked regularly to ensure safety.

Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. Monitoring of blood pressure and renal function is recommended when these agents are used together to assess the effectiveness of diuretic therapy.

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

Elderly patients may not respond differently to metoprolol tartrate and hydrochlorothiazide 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 significant 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 indicating potential risks such as 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-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, did not produce harm to the fetus, although thiazides are known to 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 providers observe neonates for these symptoms and manage them accordingly.

The estimated background risk of major birth defects and miscarriage for the general 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 approximately 2 to 4% and 15 to 20%, respectively.

Hypertension in pregnancy is associated with increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension poses fetal risks, including intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed.

Data from published observational studies did not demonstrate an association between the use of either metoprolol or hydrochlorothiazide and major congenital malformations in pregnancy. However, the findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol have methodological limitations that hinder interpretation.

In summary, while metoprolol and hydrochlorothiazide may be used during pregnancy under careful consideration, healthcare providers should remain vigilant regarding potential risks and monitor both maternal and fetal outcomes closely.

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 metoprolol or hydrochlorothiazide during lactation.

Clinically significant doses of hydrochlorothiazide have been associated with impaired 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 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 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 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 to assess renal function and adjust treatment as necessary. Regular monitoring is essential to ensure the safe and effective use of the medication in this population.

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, the most frequently observed signs include bradycardia, bradyarrhythmia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, impairment of consciousness or coma, cardiogenic shock, as well as gastrointestinal symptoms such as nausea and vomiting.

For thiazide diuretics, acute intoxication is rare; however, the primary concern in overdose situations is the acute loss of fluid, electrolytes, and magnesium. Symptoms may manifest as hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness. Altered laboratory findings may also be present, including hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN) levels.

Management of overdosage should occur in a healthcare facility equipped to provide appropriate supportive measures, monitoring, and supervision, as treatment is primarily symptomatic and supportive with no specific antidote available. Limited data indicate that neither metoprolol nor hydrochlorothiazide is dialyzable, and hemodialysis is unlikely to significantly contribute to the elimination of metoprolol. If deemed necessary, gastric lavage and/or activated charcoal may be administered.

In the event of bradycardia and conduction disturbances, treatment options include the administration of atropine, adrenergic-stimulating drugs, or the use of a pacemaker. For hypotension or shock, it is essential to address any underlying bradycardia. Considerations for treatment may include intravenous fluid expansion, vasopressors, and the injection of glucagon, followed by an intravenous infusion of glucagon if required. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be warranted.

In cases of heart failure, it is crucial to treat any present bradycardia and support hemodynamics with inotropic agents as necessary. Bronchospasm, if encountered, can typically be reversed with bronchodilators.

Nonclinical Toxicology

No teratogenic effects have been reported for metoprolol tartrate and hydrochlorothiazide. Studies indicate that metoprolol tartrate and hydrochlorothiazide 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 was observed in rats receiving metoprolol tartrate 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 in studies with doses up to 100 and 4 mg/kg/day.

Carcinogenicity and mutagenicity studies have not been conducted with metoprolol tartrate and hydrochlorothiazide. Long-term studies in animals have been performed to assess 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 incidence of spontaneously occurring benign or malignant neoplasms. The only drug-related histologic changes noted 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 three 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 or malignant tumors. This study was replicated 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. All mutagenicity tests conducted 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. However, 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. Positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, as well as in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Postmarketing Experience

Reports of side effects have been received through voluntary submissions and surveillance programs. Patients are encouraged to consult their healthcare provider for medical advice regarding any adverse effects experienced. Additionally, side effects can be reported to the FDA at 1-800-FDA-1088.

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 enhance absorption and minimize gastrointestinal discomfort. 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.

It is crucial to counsel patients not to discontinue the use of metoprolol tartrate and hydrochlorothiazide tablets without first consulting their healthcare provider, as abrupt cessation may lead to adverse effects. Patients should also be encouraged to seek medical advice regarding any side effects they may experience. They can report side effects to the FDA at 1-800-FDA-1088.

For additional information, patients may contact Alembic Pharmaceuticals Limited at 1-866-210-9797.

Storage and Handling

The product is supplied in a tight, light-resistant container, in accordance with USP standards. 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 defined by USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture to maintain its integrity and efficacy.

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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)