Lopressor Hct

Description

Lopressor HCT combines the antihypertensive effects of metoprolol tartrate, a beta adrenoreceptor blocker, and hydrochlorothiazide, a thiazide diuretic. It is formulated as tablets for oral administration, 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 contain 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. 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.

Inactive ingredients in Lopressor HCT include microcrystalline cellulose, colloidal silicon dioxide, D&C Yellow No. 10 (in 100/50 mg tablets), FD&C Blue No. 1 (in 50/25 mg tablets), FD&C Red No. 80, FD&C Yellow No. 6, FD&C Yellow No. 5 (in 100/25 mg tablets), lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate, stearic acid, and Confectioner's Sugar.

Uses and Indications

LOPRESSOR HCT 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 LOPRESSOR HCT. 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 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 presence of cardiogenic shock or decompensated heart failure contraindicates use, 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 also contraindicated unless a permanent pacemaker is in place, due to the potential for significant cardiac complications.

Anuria is a contraindication, as the medication may not be effectively eliminated, leading to potential toxicity.

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, this medication can 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 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 metoprolol and hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions associated with metoprolol include confusional state, very rare reports of hepatitis, jaundice, and non-specific hepatic dysfunction. Additionally, there have been isolated cases of elevations in transaminase, alkaline phosphatase, and lactic dehydrogenase. Patients may also experience an increase in blood triglycerides and a decrease in High-Density Lipoprotein (HDL).

Hydrochlorothiazide has been associated with several serious adverse reactions, particularly in the digestive system, including pancreatitis and intrahepatic cholestatic jaundice. Cardiovascular effects may include orthostatic hypotension, which can be exacerbated by alcohol, barbiturates, or narcotics. Neurologic adverse reactions reported include vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Musculoskeletal reactions such as muscle spasms have also been noted.

Hematologic reactions to hydrochlorothiazide can be severe, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Metabolic effects may manifest as hyperglycemia, glycosuria, and hyperuricemia. Hypersensitive reactions can include necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity.

Other beta-adrenergic agents may lead to central nervous system reactions such as reversible mental depression, visual disturbances, hallucinations, and an acute reversible syndrome characterized by disorientation, emotional lability, and decreased performance on neuropsychometric tests. Hematologic reactions may include agranulocytosis and various forms of purpura. Hypersensitive reactions can also involve laryngospasm and respiratory distress.

Additional important notes 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 advised to avoid discontinuing therapy prior to major surgery. Patients with diabetes should be monitored closely, as these medications 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 symptoms of arterial insufficiency may be aggravated. In cases of pheochromocytoma, therapy should be initiated with an alpha blocker. Abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, and patients may be unresponsive to standard doses of epinephrine used for allergic reactions.

In the event of overdosage, signs and symptoms may include bradycardia, hypotension, heart failure, cardiac conduction disturbances, bronchospasm, atrioventricular block, hypoxia, impairment of consciousness or coma, and cardiogenic shock. Nausea and vomiting may also occur. For thiazide diuretics, acute loss of fluid, electrolytes, and magnesium can lead to hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness. Altered laboratory findings such as hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased BUN may also be observed.

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

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

Withdrawal from clonidine can precipitate rebound hypertension, which should be considered when discontinuing therapy. Gradual tapering of clonidine is recommended to minimize this risk.

Antidiabetic medications may require dosage adjustments when used in conjunction with other therapies, as their effects can be altered. Close monitoring of blood glucose levels is advised to ensure optimal glycemic control.

The use of 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.

Lithium co-administration poses a risk of lithium toxicity, necessitating regular monitoring of serum lithium levels to avoid adverse effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. Patients should be monitored for changes in blood pressure and fluid retention, and alternative analgesic options should be considered if necessary.

Packaging & NDC

The table below lists all NDC Code configurations of Lopressor Hct (metoprolol tartrate and hydrochlorothiazide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

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

Geriatric Use

Clinical studies of Lopressor HCT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger patients.

Hydrochlorothiazide, a component of Lopressor HCT, is substantially excreted by the kidneys. Therefore, the risk of toxic reactions to this medication may be greater in patients with impaired renal function, which is more common among geriatric patients. Given this increased risk, careful consideration should be given to dose selection in elderly patients. It is advisable to start at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies.

Monitoring of renal function may be beneficial in this population to ensure safety and efficacy.

Pregnancy

Available data indicate that untreated hypertension during pregnancy can lead to adverse outcomes for both the mother and the fetus. 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 regarding 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 significantly higher than the recommended human dose. The combination of metoprolol tartrate and hydrochlorothiazide administered to pregnant rats from mid to late gestation through lactation also resulted in increased post-implantation loss and decreased neonatal survival. While the published literature has reported inconsistent findings regarding intrauterine growth retardation and other adverse outcomes, methodological limitations in these studies hinder definitive conclusions about drug-associated risks during pregnancy.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Therefore, it is recommended that neonates be observed for these symptoms and managed accordingly. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2 to 4% and 15 to 20%, respectively, and all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

Hypertension in pregnancy is associated with increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. It also increases fetal risks for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed to mitigate these risks.

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 limitations of these studies, including retrospective design and concomitant use of other medications, must be considered when interpreting the findings.

Lactation

There are no data on the presence of LOPRESSOR HCT 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.

Doses of hydrochlorothiazide associated with clinically significant diuresis have been linked to impaired milk production, while there is no information regarding the effects of metoprolol on milk production. Lactating mothers should monitor infants exposed to LOPRESSOR HCT through breastmilk for signs of drowsiness or poor feeding, as well as for bradycardia or somnolence.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for LOPRESSOR HCT and any potential adverse effects on the breastfed child from LOPRESSOR HCT or from the underlying maternal condition. 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 an estimated 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 hydrochlorothiazide of 275 mcg/L at 3 hours following a 50 mg dose, with no drug detected (< 20 mcg/L) in the infant’s plasma at 2 and 11 hours following the mother’s dose.

Renal Impairment

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

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 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.

Management of beta-adrenergic blocker overdosage should focus on supportive care and symptomatic treatment. Healthcare professionals are advised to monitor the patient's vital signs closely and provide appropriate interventions for bradycardia and hypotension, which may include the administration of intravenous fluids and vasopressors as necessary. In cases of bronchospasm, bronchodilators may be indicated.

For thiazide diuretics, acute intoxication is considered rare; however, when it occurs, the most prominent feature is the acute loss of fluid, electrolytes, and magnesium. Symptoms of thiazide diuretic overdose may include hypotension, dizziness, muscle cramps, renal impairment or failure, and sedation or impairment of consciousness. Altered laboratory findings are also common, potentially revealing hypokalemia, hypomagnesemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (BUN) levels.

In managing thiazide diuretic overdosage, it is crucial to restore fluid and electrolyte balance. Healthcare professionals should monitor the patient's laboratory values and provide appropriate rehydration and electrolyte replacement therapy as needed. Continuous assessment of renal function is also recommended to guide further management.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted. Lopressor HCT demonstrated no evidence of impaired fertility in both male and female rats administered gavaged doses of up to 200/50 mg/kg, which corresponds to approximately 10 and 20 times the maximum recommended human dose (MRHD) of metoprolol and hydrochlorothiazide, respectively, on a mg/m² basis. Additionally, a study in rats indicated no impaired fertility at doses up to 22 times the daily dose of 200 mg for a 60 kg patient. Hydrochlorothiazide also showed no adverse effects on fertility in mice and rats of either sex when exposed to dietary doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Carcinogenicity and mutagenicity studies have not been conducted with Lopressor HCT. Long-term studies in animals have been performed to assess the carcinogenic potential. In a 2-year study involving rats at oral dosage levels of up to 800 mg/kg per day, which is approximately 41 times the daily dose of 200 mg for a 60-kg patient on a mg/m² basis, there was no increase in the incidence of spontaneously occurring benign or malignant neoplasms. The only drug-related histologic changes observed were a mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia.

In a separate 21-month study in Swiss albino mice at oral dosage levels of up to 750 mg/kg per day, about 18 times the daily dose of 200 mg for a 60-kg patient, benign lung tumors (small adenomas) were more frequently observed 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 replicated in CD-1 mice, yielding no statistically or biologically significant differences between treated and control groups for any tumor type.

All mutagenicity tests conducted, 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, returned 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, about 120 times the MRHD of 25 mg/day on a mg/m² basis, or in male and female rats at doses up to approximately 100 mg/kg/day, about 40 times the MRHD on a mg/m² basis. However, equivocal evidence for hepatocarcinogenicity was noted 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. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were observed in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, as well as in the Aspergillus nidulans nondisjunction assay at unspecified concentrations.

Postmarketing Experience

Adverse reactions have been reported during the postmarketing experience of LOPRESSOR HCT. These reactions are derived from voluntary reports and surveillance programs, and due to the uncertain size of the reporting population, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the context of Metoprolol, the following adverse reactions have been noted: confusional state, increased blood triglycerides, and decreased High-Density Lipoprotein (HDL). Very rare instances of hepatitis, jaundice, and non-specific hepatic dysfunction have been documented, along with isolated cases of elevations in transaminase, alkaline phosphatase, and lactic dehydrogenase.

For Hydrochlorothiazide, a range of adverse reactions has been reported, categorized as follows:

Digestive: Pancreatitis, intrahepatic cholestatic jaundice, sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.

Cardiovascular: Orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, or narcotics.

Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.

Musculoskeletal: Muscle spasm.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia.

Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.

Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, and photosensitivity.

Additionally, a variety of adverse reactions associated with other beta-adrenergic blocking agents have been reported and should be considered potential adverse reactions to LOPRESSOR HCT.

In the Central Nervous System, reactions such as reversible mental depression progressing to catatonia, visual disturbances, hallucinations, and an acute reversible syndrome characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests have been observed.

Hematologic reactions include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. Hypersensitive reactions may also involve laryngospasm and respiratory distress.

Patient Counseling

Healthcare providers should inform patients or caregivers about the risk of hypoglycemia associated with Lopressor HCT, particularly in individuals who 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 Lopressor HCT as directed, specifically with or immediately following meals, to optimize its effectiveness. 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, healthcare providers must emphasize the importance of not discontinuing Lopressor HCT without prior consultation with their healthcare provider, ensuring that patients understand the necessity of maintaining communication regarding their treatment plan.

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 77ºF (25ºC), with permissible excursions between 59ºF to 86ºF (15ºC to 30ºC) as outlined by USP guidelines. It is essential to protect the product from moisture to maintain its integrity and efficacy.

Additional Clinical Information

Post-marketing experience has revealed various adverse reactions associated with LOPRESSOR HCT, which may not be reliably quantified due to the voluntary nature of reporting from a diverse population.

For metoprolol, reported adverse reactions include confusional state, increased blood triglycerides, decreased High-Density Lipoprotein (HDL), and very rare instances of hepatitis, jaundice, and non-specific hepatic dysfunction. Isolated cases of elevated transaminases, alkaline phosphatase, and lactic dehydrogenase have also been noted. Hydrochlorothiazide has been linked to a range of digestive issues such as pancreatitis, jaundice, vomiting, and diarrhea, as well as cardiovascular effects like orthostatic hypotension. Neurologic reactions include vertigo, dizziness, and transient blurred vision, while musculoskeletal effects may involve muscle spasms. Hematologic concerns encompass aplastic anemia and thrombocytopenia, and metabolic effects include hyperglycemia and hyperuricemia. Hypersensitivity reactions can manifest as necrotizing angiitis, Stevens-Johnson syndrome, and respiratory distress. Additionally, adverse reactions reported with other beta-adrenergic agents may also be relevant, including central nervous system effects such as reversible mental depression and hallucinations, as well as hematologic and hypersensitive reactions like laryngospasm.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Lopressor Hct as submitted by Validus Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)