Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide tablets, USP combine triamterene, a potassium-conserving diuretic, with the natriuretic agent hydrochlorothiazide. Each tablet contains either 75 mg of triamterene and 50 mg of hydrochlorothiazide or 37.5 mg of triamterene and 25 mg of hydrochlorothiazide. Triamterene is chemically identified as 2,4,7-triamino-6-phenylpteridine, with a molecular weight of 253.27. It is practically insoluble in water, benzene, chloroform, ether, and dilute alkali hydroxides, but is soluble in formic acid and sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol, and dilute mineral acids. Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.73. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. The tablets for oral administration also contain inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate, and microcrystalline cellulose.

Uses and Indications

This fixed combination drug is indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide alone. It is also indicated for patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked, such as those on concomitant digitalis preparations or with a history of cardiac arrhythmias.

Triamterene and hydrochlorothiazide may be administered alone or in conjunction with other antihypertensive agents, including beta-blockers. Due to the potential for enhanced effects of these medications, dosage adjustments may be necessary.

Limitations of Use: This drug is not indicated for the initial therapy of edema or hypertension, except in individuals where the risk of developing hypokalemia is unacceptable.

In pregnancy, the routine use of diuretics is inappropriate and poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating established toxemia. Thiazides may be indicated during pregnancy when edema is due to pathological causes, similar to their use in non-pregnant patients.

Dependent edema during pregnancy, resulting from mechanical factors such as venous return restriction due to an expanded uterus, should be managed through non-pharmacological means, including elevation of the lower extremities and the use of support hose. The hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there is no underlying cardiovascular disease. In cases where edema causes significant discomfort and is unresponsive to rest, a short course of diuretics may be considered appropriate.

Dosage and Administration

The usual dosage of triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg is one or two tablets daily, administered as a single dose, with appropriate monitoring of serum potassium levels. For the 75 mg/50 mg formulation, the recommended dosage is one tablet daily, also with serum potassium monitoring.

There is limited clinical experience with dosages exceeding one tablet of triamterene and hydrochlorothiazide 75 mg/50 mg daily or two tablets of triamterene and hydrochlorothiazide 37.5 mg/25 mg daily. Administration of two tablets of triamterene and hydrochlorothiazide 37.5 mg/25 mg daily in divided doses, rather than as a single dose, may increase the risk of electrolyte imbalance and renal dysfunction.

Patients currently receiving 50 mg of hydrochlorothiazide who develop hypokalemia may be transitioned directly to triamterene and hydrochlorothiazide tablets 75 mg/50 mg. Similarly, those on 25 mg of hydrochlorothiazide who experience hypokalemia may be switched to triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg.

For patients requiring hydrochlorothiazide therapy where hypokalemia is a concern, treatment may be initiated with triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg. If optimal blood pressure control is not achieved with this dosage, the dose may be increased to two tablets of triamterene and hydrochlorothiazide 37.5 mg/25 mg daily as a single dose, or one tablet of triamterene and hydrochlorothiazide 75 mg/50 mg daily. Should blood pressure remain uncontrolled, the addition of another antihypertensive agent should be considered.

Clinical studies indicate that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide at daily doses of 25 mg to 50 mg hydrochlorothiazide and 50 mg to 100 mg triamterene may be safely converted to one triamterene and hydrochlorothiazide tablet 37.5 mg/25 mg daily. It is essential that all patients transitioning from less bioavailable formulations to triamterene and hydrochlorothiazide tablets 75 mg/50 mg be closely monitored both clinically and for serum potassium levels following the switch.

Contraindications

Triamterene and hydrochlorothiazide are contraindicated in the following conditions:

Patients with hyperkalemia, defined as elevated serum potassium levels of 5.5 mEq/liter or greater, should not use this medication. If hyperkalemia occurs, discontinuation of the drug is necessary, and a thiazide alone should be considered.

The use of triamterene and hydrochlorothiazide is contraindicated in patients receiving other potassium-conserving agents, such as spironolactone or amiloride hydrochloride, as well as those on potassium supplementation through medications, potassium-containing salt substitutes, or potassium-enriched diets.

This medication is also contraindicated in patients with impaired renal function, including those with anuria, acute or chronic renal insufficiency, or significant renal impairment.

Additionally, triamterene and hydrochlorothiazide should not be administered to individuals who are hypersensitive to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs.

Warnings and Precautions

Abnormal elevation of serum potassium levels, defined as hyperkalemia (≥ 5.5 mEq/liter), can occur with the use of potassium-conserving diuretic combinations, including triamterene and hydrochlorothiazide. The risk of hyperkalemia is heightened in patients with renal impairment, diabetes (even in the absence of renal impairment), as well as in elderly or severely ill patients. Due to the potential fatality associated with uncorrected hyperkalemia, it is imperative that serum potassium levels be monitored at frequent intervals, particularly in patients initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of any condition that may affect renal function.

Patients receiving triamterene and hydrochlorothiazide should be closely monitored for fluid and electrolyte imbalances, including but not limited to hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Regular determination of serum electrolytes is essential to identify any potential imbalances, and this should be conducted at appropriate intervals. Serum and urine electrolyte assessments are particularly critical in patients experiencing vomiting or those receiving parenteral fluids. Clinicians should be vigilant for warning signs or symptoms indicative of fluid and electrolyte imbalance, which may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

The administration of triamterene and hydrochlorothiazide may lead to elevated blood urea nitrogen (BUN) and creatinine levels. Therefore, periodic assessments of BUN and creatinine are recommended, especially for elderly patients and those with suspected or confirmed hepatic disease or renal insufficiencies. Should azotemia increase, it is advised that triamterene and hydrochlorothiazide be discontinued.

In cases where hyperkalemia is suspected, characterized by symptoms such as paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock, an electrocardiogram (ECG) should be obtained promptly. If hyperkalemia is confirmed, triamterene and hydrochlorothiazide must be discontinued immediately, and a thiazide diuretic alone should be considered as a substitute. Additionally, if there is an increase in azotemia, discontinuation of triamterene and hydrochlorothiazide is warranted.

Side Effects

Side effects observed in association with the use of triamterene and hydrochlorothiazide, as well as other combination products containing these agents, include a range of adverse reactions categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, photosensitivity, and respiratory distress, including pneumonitis. Hematologic reactions such as agranulocytosis, aplastic anemia, and hemolytic anemia have also been reported. Renal complications, including acute renal failure and acute interstitial nephritis, may occur. Patients may experience tachycardia, shortness of breath, and chest pain, particularly in the context of orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, or narcotics.

Common adverse reactions encompass a variety of systems. Gastrointestinal effects include nausea, vomiting, diarrhea, constipation, and appetite disturbances, along with more severe conditions such as jaundice and pancreatitis. Central nervous system effects may manifest as drowsiness, fatigue, insomnia, headache, dizziness, and anxiety. Patients may also report muscle cramps, weakness, and decreased sexual performance.

Altered laboratory findings are notable, with potential for hyperkalemia, hypokalemia, hyponatremia, and hypomagnesemia. Reversible elevations in blood urea nitrogen (BUN) and serum creatinine have been observed in hypertensive patients treated with triamterene and hydrochlorothiazide. Additionally, hyperglycemia, glycosuria, and elevated liver enzymes have been reported.

Postmarketing experience has indicated an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses. The risk for SCC in the overall population is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥ 50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

Monitoring of serum potassium levels is critical, as hyperkalemia (serum potassium levels ≥ 5.5 mEq/liter) can occur with potassium-conserving diuretic combinations, particularly in patients with renal impairment, diabetes, or those who are elderly or severely ill. Uncorrected hyperkalemia may be fatal, necessitating frequent monitoring, especially when initiating treatment or adjusting dosages.

Drug Interactions

Thiazide diuretics may enhance the effects of other antihypertensive agents, potentially leading to additive hypotensive effects. Clinicians should monitor blood pressure closely when initiating or adjusting therapy with thiazides in conjunction with other antihypertensives.

In terms of pharmacodynamic interactions, thiazides can diminish arterial responsiveness to norepinephrine; however, this does not compromise the efficacy of norepinephrine as a pressor agent. Additionally, thiazides have been observed to increase the responsiveness to neuromuscular blocking agents such as tubocurarine, necessitating careful monitoring of neuromuscular function during concurrent use.

Lithium therapy is contraindicated with diuretics, including thiazides, due to the potential for reduced renal clearance of lithium, which significantly raises the risk of lithium toxicity. Regular monitoring of lithium levels is recommended for patients requiring both therapies.

Caution is warranted when combining indomethacin with triamterene and hydrochlorothiazide, as acute renal failure has been reported in such cases. Clinicians should consider alternative therapies or closely monitor renal function in patients receiving this combination.

Lastly, potassium-sparing diuretics should be used with caution alongside ACE inhibitors due to an increased risk of hyperkalemia. Frequent monitoring of serum potassium levels is advised to prevent potential complications associated with elevated potassium.

Packaging & NDC

The table below lists all NDC Code configurations of Triamterene 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, particularly those aged 65 and older, are at an increased risk for hyperkalemia, especially if they have underlying renal impairment or diabetes. It is essential to monitor serum potassium levels at frequent intervals in this population, particularly when initiating treatment with triamterene and hydrochlorothiazide, when dosages are adjusted, or during any illness that may affect renal function.

Cumulative drug effects may be more pronounced in elderly patients with impaired renal function. Studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced in this demographic, leading to increased plasma levels following administration.

Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, especially for elderly patients, those with suspected or confirmed hepatic disease, or individuals with renal insufficiencies. These monitoring practices are crucial to ensure the safe and effective use of the medication in geriatric patients.

Pregnancy

There are no studies conducted on the effects of triamterene and hydrochlorothiazide tablets, the triamterene/hydrochlorothiazide combination, or triamterene alone on animal reproductive function. However, data from studies involving hydrochlorothiazide indicate that it did not adversely affect the fertility of mice and rats of either sex when these animals were exposed to doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation. The corresponding multiples of the maximum recommended human dose (MRHD) are 100 for mice and 4 for rats based on body weight, and 9.4 for mice and 0.8 for rats based on body surface area.

Given the lack of specific studies on the combination and the limited data available, healthcare professionals should exercise caution when prescribing this medication to pregnant patients. The potential risks to fetal outcomes remain unclear, and the absence of comprehensive reproductive studies necessitates careful consideration of the benefits and risks in women of childbearing potential.

Lactation

Thiazides and triamterene in combination have not been studied in nursing mothers. However, triamterene appears in animal milk, suggesting that it may also be excreted in human breast milk. Thiazides are known to be excreted in human breast milk as well.

If the use of the combination drug product is deemed essential, it is recommended that the lactating mother discontinue breastfeeding.

Renal Impairment

Patients with renal impairment are at an increased risk for hyperkalemia, particularly those with diabetes, elderly patients, or those who are severely ill. Serum potassium levels should be monitored at frequent intervals, especially when initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of any illness that may affect renal function.

The risk of hyperkalemia associated with potassium-sparing diuretics is heightened in patients with reduced kidney function. For patients with mild renal functional impairment, the use of this medication should be approached with caution, necessitating frequent and ongoing monitoring of serum electrolytes.

Cumulative drug effects may occur in individuals with impaired renal function, as evidenced by reduced renal clearances of hydrochlorothiazide and the active metabolite of triamterene, leading to increased plasma levels in elderly patients and those with renal impairment. If hyperkalemia is suspected, an electrocardiogram (ECG) should be performed. In cases where hyperkalemia is confirmed, triamterene and hydrochlorothiazide should be discontinued immediately, and a thiazide diuretic alone should be considered as a substitute.

In diabetic patients receiving triamterene and hydrochlorothiazide, serum electrolytes must be monitored closely. Additionally, potassium-conserving therapies should be avoided in severely ill patients who may experience respiratory or metabolic acidosis. Frequent evaluations of acid/base balance and serum electrolytes are essential when administering this combination in patients with acidosis.

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 triamterene and hydrochlorothiazide, it is important to note that specific data regarding human overdosage are lacking, and no specific antidote is available. The primary concern in overdose situations is the potential for fluid and electrolyte imbalances.

Excessive doses of triamterene may lead to symptoms such as hyperkalemia, dehydration, nausea, vomiting, weakness, and possibly hypotension. Conversely, overdose with hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, and lethargy, which may progress to coma, as well as gastrointestinal irritation.

Management of an overdose is primarily symptomatic and supportive. It is recommended that therapy with triamterene and hydrochlorothiazide be discontinued immediately. In cases of significant overdose, healthcare professionals may consider inducing emesis or performing gastric lavage to reduce the absorption of the drugs.

Continuous monitoring of serum electrolyte levels and fluid balance is essential in managing overdose cases. Supportive measures should be implemented as necessary to maintain hydration, electrolyte balance, and the proper functioning of respiratory, cardiovascular, and renal systems.

Nonclinical Toxicology

The safe use of triamterene and hydrochlorothiazide during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women. Therefore, these medications should only be used in pregnancy if the potential benefits outweigh the risks to the fetus. Reproductive studies conducted in rats at doses up to 20 times the Maximum Recommended Human Dose (MRHD) based on body weight, and 6 times the MRHD based on body surface area, did not demonstrate any harm to the fetus from triamterene. Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 mg/kg/day for mice and 1000 mg/kg/day for rats. At these doses, which are significantly higher than the MRHD, no evidence of fetal harm was observed. However, due to the lack of adequate studies in pregnant women and the unpredictability of animal reproduction studies in predicting human outcomes, caution is advised.

Thiazides and triamterene have been shown to cross the placental barrier and can be detected in cord blood. The use of these medications in pregnant women necessitates careful consideration of the anticipated benefits against potential risks to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

Long-term studies evaluating the safety of triamterene and hydrochlorothiazide tablets have not been conducted. In studies overseen by the National Toxicology Program, rats were fed diets containing varying concentrations of triamterene, while mice were similarly exposed. Male and female rats at the highest concentration received approximately 25 and 30 mg/kg/day, respectively, while male and female mice received about 45 and 60 mg/kg/day. An increased incidence of hepatocellular neoplasia, primarily adenomas, was noted in male and female mice at the highest dosage level. These doses correspond to 7.5 times and 10 times the MRHD for male and female mice, respectively, based on body weight, and 0.7 times and 0.9 times the MRHD based on body surface area. In contrast, hepatocellular neoplasia in rats was limited to males and did not show a dose-dependent relationship, with no statistically significant differences from control groups at any dose level.

Two-year feeding studies in mice and rats, also conducted under the National Toxicology Program, evaluated hydrochlorothiazide at doses up to 600 mg/kg/day for mice and 100 mg/kg/day for rats. These doses represent 600 times and 100 times the MRHD for hydrochlorothiazide, respectively, based on body weight. No evidence of carcinogenic potential was found in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was observed in male mice.

Studies assessing the mutagenic potential of triamterene and hydrochlorothiazide have not been performed. Triamterene was not found to be mutagenic in various strains of bacteria, nor did it induce chromosomal aberrations in Chinese hamster ovary (CHO) cells. However, it did induce sister chromatid exchanges in CHO cells. Hydrochlorothiazide was not genotoxic in several in vitro assays, including the Ames test and tests for chromosomal aberrations. Positive results were noted in the CHO sister chromatid exchange test and mouse lymphoma cell assays at specific concentrations. Additionally, hydrochlorothiazide did not adversely affect fertility in mice and rats at doses up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation, corresponding to multiples of the MRHD of 100 for mice and 4 for rats based on body weight.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer. Data from a study conducted within the Sentinel System indicate that this increased risk is primarily observed for squamous cell carcinoma (SCC), particularly among white patients who have received large cumulative doses of the medication. The overall population shows an approximate increase of 1 additional case of SCC per 16,000 patients per year. Notably, for white patients who have taken a cumulative dose of 50,000 mg or more, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing, using sunscreen with a high SPF, and avoiding prolonged sun exposure, especially during peak hours.

Additionally, healthcare providers should emphasize the importance of regular skin cancer screenings for patients on this medication. Patients should be made aware of the potential increased risk of skin cancer associated with hydrochlorothiazide and encouraged to report any unusual skin changes or lesions to their healthcare provider promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to maintain its integrity and efficacy.

Additional Clinical Information

Patients receiving hydrochlorothiazide should have serum electrolytes monitored at appropriate intervals to detect potential imbalances, particularly during episodes of vomiting or when receiving parenteral fluids. Frequent serum and urine electrolyte determinations are essential in these situations. Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, especially for elderly patients or those with suspected or confirmed hepatic or renal insufficiencies.

Clinicians should counsel patients on the importance of sun protection and regular skin cancer screenings while taking hydrochlorothiazide. It is important to note that hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving high cumulative doses. The risk for SCC in the general population is estimated at one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of 50,000 mg or more, the risk increases to one additional case for every 6,700 patients per year.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Triamterene and Hydrochlorothiazide as submitted by Advagen Pharma Ltd. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)