Metoprolol tartrate/Hydrochlorothiazide

Description

Metoprolol tartrate and hydrochlorothiazide tablets combine the antihypertensive effects of metoprolol tartrate, a selective beta 1-adrenoreceptor blocking agent, with the antihypertensive and diuretic properties of hydrochlorothiazide. These tablets are formulated for oral administration and are available in three strengths: 50/25, 100/25, and 100/50.

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

Inactive ingredients in the formulation include colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, povidone, lactose, and pregelatinized starch.

Uses and Indications

Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the management of hypertension. This fixed-combination drug is not intended for initial therapy of hypertension. When the fixed combination reflects a dose that has been titrated to meet the individual patient’s needs, it may offer a more convenient alternative to administering the separate components.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

Dosage should be determined by individual titration based on the patient's response and clinical condition. Hydrochlorothiazide is typically administered at a dosage range of 12.5 to 50 mg per day. Dosing regimens exceeding 50 mg per day are not recommended.

For metoprolol tartrate tablets, the usual initial dosage is 100 mg daily, which may be given in a single or divided dose. The effective dosage range for metoprolol tartrate is between 100 and 450 mg per day. While once-daily dosing can be effective, it is important to note that lower doses, particularly 100 mg, may not sustain a full therapeutic effect over a 24-hour period. Therefore, larger or more frequent daily doses may be necessary to achieve optimal blood pressure control.

The following dosage schedule may be utilized for metoprolol tartrate tablets:

• For tablets of 50/25 mg: Administer 2 tablets per day in single or divided doses.

• For tablets of 100/25 mg: Administer 1 to 2 tablets per day in single or divided doses.

• For tablets of 100/50 mg: Administer 1 tablet per day in single or divided doses.

If additional antihypertensive therapy is required, it may be introduced gradually, starting with 50% of the usual recommended starting dose to minimize the risk of excessive hypotension. Dosage adjustments should be made based on the patient's blood pressure response and tolerability.

Contraindications

Metoprolol tartrate tablets are contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt cardiac failure, hypersensitivity to metoprolol tartrate and related derivatives, or to any of the excipients. Additionally, hypersensitivity to other beta blockers is a concern due to potential cross-sensitivity. Use is also contraindicated in individuals with sick-sinus syndrome and severe peripheral arterial circulatory disorders.

Hydrochlorothiazide is contraindicated in patients with anuria and those with hypersensitivity to this or other sulfonamide-derived drugs.

Warnings and Precautions

Patients receiving metoprolol should be closely monitored for several critical warnings and precautions to ensure safe and effective use of the medication.

Cardiac Failure In patients with congestive heart failure, sympathetic stimulation is essential for maintaining myocardial contractility. Therefore, metoprolol should be administered with caution in hypertensive patients who have controlled congestive heart failure. In individuals without a history of cardiac failure, continued beta-blockade may precipitate cardiac failure. At the first indication of impending cardiac failure, it is imperative that patients are fully digitalized and/or treated with a diuretic. If cardiac failure persists despite these interventions, metoprolol should be discontinued.

Ischemic Heart Disease Abrupt discontinuation of metoprolol may exacerbate angina pectoris or lead to myocardial infarction. Patients must be advised against interrupting therapy without consulting their physician.

Bronchospastic Diseases Beta blockers are generally contraindicated in patients with bronchospastic diseases. If metoprolol is deemed necessary, it should be administered cautiously and in conjunction with a beta-2-stimulating agent.

Major Surgery It is not recommended to routinely withdraw beta-blocking therapy prior to major surgical procedures, as this may impair the heart's response to adrenergic stimuli, thereby increasing the risks associated with anesthesia and surgery.

Diabetes and Hypoglycemia Caution is advised when prescribing metoprolol to diabetic patients, as the medication may mask the symptoms of hypoglycemia.

Pheochromocytoma In patients with pheochromocytoma, metoprolol should only be used in conjunction with an alpha blocker, which must be initiated prior to the beta blocker to prevent a paradoxical increase in blood pressure.

Thyrotoxicosis Beta blockade can obscure the signs of hyperthyroidism. Abrupt withdrawal of metoprolol in these patients should be avoided to prevent the risk of thyroid storm.

General Precautions Metoprolol should be used with caution in individuals with impaired hepatic function. Patients on thiazide therapy must be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs of electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, tachycardia, and gastrointestinal disturbances. Hypokalemia may occur, particularly with brisk diuresis or severe cirrhosis, and potassium supplementation may be necessary. Additionally, hyperuricemia or gout should be monitored in patients receiving thiazide therapy, and latent diabetes may emerge during treatment. If progressive renal impairment is observed, consideration should be given to withholding or discontinuing diuretic therapy.

Laboratory Tests Clinical laboratory evaluations may reveal elevated serum transaminase, alkaline phosphatase, and lactate dehydrogenase levels in patients taking metoprolol. Initial and periodic serum electrolyte determinations are recommended to identify potential imbalances, particularly in patients experiencing excessive vomiting or receiving parenteral fluids.

Side Effects

Adverse reactions associated with Metoprolol Tartrate and Hydrochlorothiazide have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by their seriousness and frequency.

Common adverse reactions, occurring in approximately 10% of patients, include fatigue or lethargy, flu syndrome, dizziness or vertigo, drowsiness or somnolence, headache, and bradycardia. Other common reactions, each occurring in about 1% of patients, include decreased exercise tolerance, dyspnea, diarrhea, digestive disorders, dry mouth, nausea or vomiting, constipation, hypokalemia, edema, gout, anorexia, blurred vision, tinnitus, earache, sweating, purpura, and impotence.

Serious adverse reactions reported include agranulocytosis, aplastic anemia, and thrombocytopenia, which have been documented in both Metoprolol and Hydrochlorothiazide. Additionally, there are very rare reports of gangrene in patients with pre-existing severe peripheral circulatory disorders, as well as acute reversible syndromes characterized by disorientation, short-term memory loss, and emotional lability.

In the central nervous system, participants have reported tiredness, dizziness, depression, mental confusion, and short-term memory loss, with nightmares noted but the drug relationship remaining unclear. Cardiovascular effects such as shortness of breath and cold extremities have been reported in approximately 3% of patients, while very rare instances of congestive heart failure and intensification of AV block have also been documented.

Gastrointestinal adverse reactions include vomiting, which is a common occurrence, as well as diarrhea, nausea, gastric pain, constipation, flatulence, and heartburn, with postmarketing experiences revealing very rare cases of hepatitis and jaundice.

Hypersensitive reactions have been noted, including pruritus, rash, and very rare instances of photosensitivity and worsening of psoriasis. Neurologic effects such as vertigo, transient blurred vision, paresthesia, and weakness have also been reported.

Metabolic reactions include hyperglycemia, glycosuria, and hyperuricemia. Patients have also reported muscle spasms and muscle pain, as well as fatigue and lethargy.

Overall, while many adverse reactions are common and generally mild, serious reactions, particularly hematologic and hypersensitive reactions, warrant careful monitoring in patients receiving Metoprolol Tartrate and Hydrochlorothiazide.

Drug Interactions

Concomitant use of metoprolol with catecholamine-depleting drugs, such as reserpine, may result in an additive effect, necessitating close monitoring for hypotension or significant bradycardia, which could lead to symptoms such as vertigo, syncope, or postural hypotension.

When metoprolol is used alongside digitalis glycosides, both agents can slow atrioventricular conduction and decrease heart rate, thereby increasing the risk of bradycardia. Patients with a history of severe anaphylactic reactions may exhibit heightened reactivity to allergens while on beta blockers, potentially rendering them unresponsive to standard doses of epinephrine used in allergic emergencies. Additionally, certain inhalation anesthetics may amplify the cardiodepressant effects of beta blockers.

Metoprolol is metabolized by the CYP2D6 enzyme, and the presence of potent CYP2D6 inhibitors—such as specific antidepressants (e.g., fluoxetine, paroxetine, bupropion), antipsychotics (e.g., thioridazine), antiarrhythmics (e.g., quinidine, propafenone), antiretrovirals (e.g., ritonavir), antihistamines (e.g., diphenhydramine), antimalarials (e.g., hydroxychloroquine, quinidine), antifungals (e.g., terbinafine), and ulcer medications (e.g., cimetidine)—may elevate plasma concentrations of metoprolol, warranting dosage adjustments and careful monitoring.

In patients receiving both clonidine and metoprolol, it is advised that metoprolol be discontinued several days prior to the withdrawal of clonidine to mitigate the risk of rebound hypertension.

Hydrochlorothiazide may induce hypokalemia, which can heighten the heart's sensitivity to the toxic effects of digitalis, leading to increased ventricular irritability. The risk of hypokalemia may be exacerbated by concurrent use of steroids or ACTH. In diabetic patients, insulin requirements may fluctuate—potentially increasing, decreasing, or remaining unchanged.

Thiazide diuretics can diminish arterial responsiveness to norepinephrine, although this effect does not significantly impede the therapeutic efficacy of norepinephrine. Conversely, thiazides may enhance responsiveness to tubocurarine. Furthermore, thiazides reduce renal clearance of lithium, increasing the risk of lithium toxicity. Rare instances of hemolytic anemia have been reported with the combined use of hydrochlorothiazide and methyldopa.

Concurrent administration of certain nonsteroidal anti-inflammatory agents may attenuate the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Additionally, the absorption of hydrochlorothiazide can be significantly impaired by anionic exchange resins, with cholestyramine and colestipol resins reducing gastrointestinal absorption by up to 85% and 43%, respectively.

Thiazides may also lower serum levels of protein-bound iodine without causing thyroid disturbances, and it is recommended to discontinue thiazides prior to conducting tests for parathyroid function.

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 the potential risks and benefits before prescribing this medication to pediatric patients.

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 these age groups.

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 is advisable to mitigate risks associated with renal impairment (refer to WARNINGS).

In general, when prescribing for elderly patients, it is recommended to adopt a cautious approach to dose selection. Initiating treatment at the lower end of the dosing range is prudent, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other medications.

Pregnancy

Metoprolol tartrate and hydrochlorothiazide tablets are classified as Pregnancy Category C. Animal studies have shown no evidence of adverse effects on pregnancy or fetal development when metoprolol tartrate and hydrochlorothiazide were administered to rats at doses up to 200/50 mg/kg during the organogenesis period. However, increased postimplantation loss and decreased postnatal survival were observed when these doses were given later in pregnancy (gestation days 15 to 21). In rabbit studies, increased fetal loss occurred with oral doses of 25/6.25 mg/kg, although lower doses did not show this effect.

There are no adequate and well-controlled studies of metoprolol tartrate and hydrochlorothiazide tablets in pregnant women. Therefore, these tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Metoprolol has been associated with increased postimplantation loss and decreased neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm fetal exposure to metoprolol, but no evidence of teratogenicity has been observed.

Hydrochlorothiazide has been administered orally to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, without evidence of harm to the fetus. It is important to note that thiazides cross the placental barrier and can appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults.

Lactation

Metoprolol is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also excreted in breast milk.

If the use of metoprolol tartrate and hydrochlorothiazide tablets is deemed essential, lactating mothers should discontinue nursing.

Renal Impairment

Patients with renal impairment should be monitored closely when prescribed thiazides, particularly those with severe renal disease. Caution is advised, as thiazides may precipitate azotemia in this population. Additionally, the cumulative effects of the drug can develop in patients with impaired renal function, necessitating careful assessment and potential dosing adjustments based on individual renal status.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired liver function or progressive liver disease, there is a risk that even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to mitigate potential complications. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's clinical status.

Overdosage

Several cases of overdosage with metoprolol have been reported, with some instances resulting in death. In contrast, no fatalities have been associated with hydrochlorothiazide. The oral LD50 values for metoprolol are 1158 mg/kg in mice and 3090 mg/kg in rats, while hydrochlorothiazide has an LD50 of 2750 mg/kg.

Signs and Symptoms

The potential signs and symptoms of metoprolol overdosage include:

• Cardiovascular: Bradycardia, hypotension, bronchospasm, and cardiac failure. Tachycardia, hypotension, and shock may also be observed.

• Neuromuscular: Weakness, confusion, dizziness, calf muscle cramps, paresthesia, fatigue, and impairment of consciousness.

• Digestive: Nausea, vomiting, and thirst.

• Renal: Polyuria, oliguria, or anuria due to hemoconcentration.

Hydrochlorothiazide overdosage primarily manifests as an acute loss of fluid and electrolytes. Laboratory findings may reveal hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN), particularly in patients with renal insufficiency. It is important to note that signs and symptoms may be exacerbated or altered by the concomitant use of antihypertensive medications, barbiturates, curare, digitalis (which can cause hypokalemia), corticosteroids, narcotics, or alcohol.

Management

There is no specific antidote for overdosage of metoprolol or hydrochlorothiazide. Recommended management strategies include:

• Elimination of the Drug: Induction of vomiting, gastric lavage, and administration of activated charcoal should be employed to facilitate drug elimination.

• Bradycardia: Atropine should be administered. If there is no response to vagal blockade, isoproterenol may be cautiously administered.

• Hypotension: Elevate the patient’s legs and replace lost fluids and electrolytes (potassium, sodium). A vasopressor, such as levarterenol or dopamine, may be necessary.

• Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline derivative.

• Cardiac Failure: A digitalis glycoside and diuretic should be given. In cases of shock due to inadequate cardiac contractility, dobutamine, isoproterenol, or glucagon may be considered.

Continuous monitoring of fluid and electrolyte balance, particularly serum potassium, as well as renal function, is essential until the patient's condition stabilizes.

Nonclinical Toxicology

Carcinogenicity and mutagenicity studies have not been conducted with metoprolol tartrate and hydrochlorothiazide tablets. Long-term studies in animals have been performed to evaluate the carcinogenic potential of metoprolol tartrate. In a 2-year study in 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 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 per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. However, there was no increase in malignant or total (benign plus malignant) lung tumors, or 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 mutagenicity tests performed, 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. No evidence of impaired fertility due to metoprolol was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of 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, the NTP found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Postmarketing Experience

During postapproval use of metoprolol, the following adverse reactions have been reported: confusional state, an increase in blood triglycerides, and a decrease in High-Density Lipoprotein (HDL). These reports have been collected from a population of uncertain size and are subject to confounding factors, making it impossible to reliably estimate their frequency.

Patient Counseling

Patients should be advised to take metoprolol tartrate and hydrochlorothiazide tablets regularly and continuously, as directed, with or immediately following meals. It is important for patients to understand that if a dose is missed, they should take only the next scheduled dose and not double the dose to make up for the missed one.

Patients must not discontinue metoprolol tartrate and hydrochlorothiazide tablets without first consulting their physician, as abrupt cessation may lead to adverse effects. Additionally, patients should be cautioned against operating automobiles and machinery or engaging in other tasks that require alertness until their response to therapy with metoprolol tartrate and hydrochlorothiazide has been fully assessed.

In the event of any difficulty in breathing, patients should promptly contact their physician. Furthermore, patients should inform their physician or dentist about their use of metoprolol tartrate and hydrochlorothiazide tablets prior to any surgical procedures.

Storage and Handling

The product is supplied in a tight, light-resistant container, in accordance with USP standards. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F). It is essential to protect the product from moisture to maintain its integrity and efficacy.

Additional Clinical Information

Clinical laboratory findings in patients receiving Metoprolol may reveal elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. For those on Hydrochlorothiazide, it is essential to conduct initial and periodic serum electrolyte determinations to monitor for potential electrolyte imbalances, particularly in cases of excessive vomiting or when patients are receiving parenteral fluids. Regular monitoring of serum and urine electrolytes is advised to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)