Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide tablets, USP, are formulated to combine triamterene, a potassium-conserving diuretic, with hydrochlorothiazide, a natriuretic agent. Each tablet contains either 75 mg of triamterene and 50 mg of hydrochlorothiazide or 37.5 mg of triamterene and 25 mg of hydrochlorothiazide.

For oral administration, the tablets include inactive ingredients such as colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate, and microcrystalline cellulose.

Triamterene, with a chemical structure of 2,4,7-triamino-6-phenylpteridine, has a molecular weight of 253.27 g/mol. It is practically insoluble in water, benzene, chloroform, ether, and dilute alkali hydroxides, while being soluble in formic acid and sparingly soluble in methoxyethanol. It exhibits very slight solubility in acetic acid, alcohol, and dilute mineral acids.

Hydrochlorothiazide, identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, has a molecular weight of 297.73 g/mol. It is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. Hydrochlorothiazide is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids.

Uses and Indications

This fixed combination drug is indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone. It is not indicated for the initial therapy of edema or hypertension except in individuals where the risk of developing hypokalemia cannot be tolerated.

Triamterene and hydrochlorothiazide is also indicated for patients who require a thiazide diuretic and are at risk for hypokalemia, such as those on concomitant digitalis preparations or with a history of cardiac arrhythmias. This medication may be used alone or in combination with other antihypertensive agents, including beta-blockers; however, dosage adjustments may be necessary due to potential enhancement of the actions of these drugs.

Limitations of Use: The routine use of diuretics in otherwise healthy pregnant women is inappropriate and poses unnecessary risks to both 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.

In cases of edema during pregnancy, which may arise from pathological causes or physiological changes, thiazides are indicated only when the edema is due to pathological conditions. Dependent edema resulting from venous return restriction by the expanded uterus should be managed through elevation of the lower extremities and the use of support hose, as the use of diuretics to lower intravascular volume in this context is illogical and unnecessary.

While hypervolemia during normal pregnancy is generally not harmful to the mother or fetus in the absence of cardiovascular disease, it is associated with edema in many pregnant women. If this edema causes discomfort, increased recumbency may provide relief. In rare instances where extreme discomfort is experienced and not alleviated by rest, a short course of diuretics may be 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 the administration of more than one tablet of triamterene and hydrochlorothiazide 75 mg/50 mg daily or more than two tablets of triamterene and hydrochlorothiazide 37.5 mg/25 mg daily. It is important to note that administering 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.

For patients currently receiving 50 mg of hydrochlorothiazide who develop hypokalemia, a direct transfer to triamterene and hydrochlorothiazide tablets 75 mg/50 mg is recommended. Similarly, patients on 25 mg of hydrochlorothiazide who become hypokalemic may be transitioned directly to triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg. In cases where hydrochlorothiazide therapy is necessary and hypokalemia poses a risk, treatment may be initiated with triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg.

If optimal blood pressure control is not achieved with triamterene and hydrochlorothiazide tablets 37.5 mg/25 mg, the dosage may be increased to two tablets 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, with daily doses ranging from 25 mg to 50 mg of hydrochlorothiazide and 50 mg to 100 mg of triamterene, may be safely transitioned to one triamterene and hydrochlorothiazide tablet 37.5 mg/25 mg daily. All patients switched from less bioavailable formulations to triamterene and hydrochlorothiazide tablets 75 mg/50 mg should be closely monitored both clinically and for serum potassium levels following the transfer.

Contraindications

Triamterene and hydrochlorothiazide are contraindicated in the following situations:

Use is contraindicated in patients with elevated serum potassium levels (≥ 5.5 mEq/liter) due to the risk of hyperkalemia. The combination should not be administered to patients receiving other potassium-conserving agents, such as spironolactone or amiloride hydrochloride, as this may further increase serum potassium levels. Concomitant potassium supplementation, including medications, potassium-containing salt substitutes, or potassium-enriched diets, is also contraindicated.

The use of triamterene and hydrochlorothiazide is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment, as these conditions may exacerbate renal function and increase the risk of adverse effects. Additionally, the combination should not be used in individuals who are hypersensitive to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs due to the potential for severe allergic reactions.

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), elderly individuals, or those who are severely ill. Given the potential for uncorrected hyperkalemia to be fatal, it is imperative that serum potassium levels are monitored at frequent intervals, particularly in patients initiating therapy 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 hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Regular determination of serum electrolytes is essential to detect possible imbalances, especially during episodes of vomiting or when patients are receiving parenteral fluids. Clinicians should be vigilant for warning signs of fluid and electrolyte imbalance, which may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Triamterene and hydrochlorothiazide may lead to elevated blood urea nitrogen (BUN) and creatinine levels, likely due to a reversible reduction in glomerular filtration rate or depletion of intravascular fluid volume rather than renal toxicity. Such elevations may occur more frequently in patients receiving divided dose diuretic therapy. Therefore, periodic assessments of BUN and creatinine levels are recommended, particularly for elderly patients or those with suspected or confirmed hepatic disease or renal insufficiencies. Should azotemia increase, discontinuation of triamterene and hydrochlorothiazide is advised.

Caution is warranted when prescribing triamterene and hydrochlorothiazide to patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance could precipitate hepatic coma. Additionally, triamterene has been associated with the formation of renal stones in conjunction with other calculus components; thus, it should be used judiciously in patients with a history of renal lithiasis.

As a weak folic acid antagonist, triamterene may contribute to the development of megaloblastosis in patients with diminished folic acid stores. In such cases, periodic blood evaluations are recommended. Furthermore, hyperuricemia may occur, and acute gout may be precipitated in certain patients undergoing thiazide therapy.

To ensure patient safety, serum potassium levels must be monitored closely, particularly in patients initiating treatment, during dosage modifications, or in the presence of any illness affecting renal function. Regular assessments of serum electrolytes are also necessary to identify potential imbalances. Periodic BUN and creatinine evaluations should be conducted, especially in elderly patients or those with suspected or confirmed hepatic or renal impairments.

In the event of suspected hyperkalemia, characterized by symptoms such as paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, or shock, an electrocardiogram (ECG) should be obtained promptly. If hyperkalemia is confirmed, triamterene and hydrochlorothiazide should be discontinued immediately, and a thiazide diuretic alone should be considered as a substitute. If serum potassium levels exceed 6.5 mEq/liter, more aggressive therapeutic measures are required.

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 events such as agranulocytosis, thrombocytopenia, and aplastic anemia have also been reported. Renal complications, including acute renal failure and acute interstitial nephritis, may occur. Patients may experience severe gastrointestinal reactions, such as jaundice and pancreatitis.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal symptoms like nausea, vomiting, diarrhea, and abdominal cramping. Central nervous system effects such as drowsiness, fatigue, headache, and dizziness are also frequently observed. Cardiovascular reactions, including tachycardia and orthostatic hypotension, may occur, particularly in patients who consume alcohol or narcotics.

Altered laboratory findings are notable, with serum electrolyte imbalances such as hyperkalemia, hypokalemia, and hyponatremia being significant. Reversible elevations in blood urea nitrogen (BUN) and serum creatinine have been observed in hypertensive patients treated with triamterene and hydrochlorothiazide. Additionally, hyperglycemia and glycosuria have been reported, with some patients developing diabetes mellitus. Elevated liver enzymes have also been noted in patients receiving these medications.

Postmarketing data indicate an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The risk for SCC in the general population is approximately 1 additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥ 50,000 mg, the risk increases to approximately 1 additional case for every 6,700 patients per year.

Patients should be monitored for hyperkalemia, particularly those with renal impairment, diabetes, or those who are elderly or severely ill, as uncorrected hyperkalemia may be fatal. Regular monitoring of serum potassium levels is essential, especially when initiating treatment, changing dosages, or during any illness that may affect renal function.

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 patients already receiving antihypertensive medications.

Thiazides can diminish arterial responsiveness to norepinephrine; however, this effect does not compromise the therapeutic efficacy of norepinephrine as a pressor agent. Additionally, thiazides have been observed to increase responsiveness to neuromuscular blocking agents such as tubocurarine, which may necessitate adjustments in dosing or monitoring of neuromuscular function during concurrent use.

Concomitant use of lithium with diuretics, including thiazides, is generally contraindicated due to the potential for reduced renal clearance of lithium, significantly increasing the risk of lithium toxicity. It is advisable to consult the lithium package insert for specific guidance on managing such interactions.

Caution is warranted when administering non-steroidal anti-inflammatory drugs (NSAIDs) alongside formulations containing triamterene and hydrochlorothiazide, as acute renal failure has been reported in some patients. Monitoring of renal function is recommended in these cases.

The combination of potassium-sparing agents with angiotensin-converting enzyme (ACE) inhibitors should be approached with extreme caution due to a markedly elevated risk of hyperkalemia. Frequent monitoring of serum potassium levels is essential to mitigate this risk and ensure patient safety.

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 may experience an increased risk of hyperkalemia, particularly those with renal impairment or diabetes. It is essential to monitor serum potassium levels at frequent intervals in this population, especially when dosages are adjusted or during any illness that may affect renal function.

Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced in elderly patients, leading to increased plasma levels of these medications. Therefore, careful consideration should be given to dosage adjustments in geriatric patients to mitigate potential adverse effects.

Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, particularly for elderly patients, as well as those with suspected or confirmed hepatic disease or renal insufficiencies. Regular monitoring is crucial to ensure the safety and efficacy of treatment in this vulnerable population.

Pregnancy

There are no studies available assessing 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 fertility in 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 or triamterene alone, healthcare professionals should exercise caution when prescribing this medication to pregnant patients. The potential risks to fetal outcomes remain unclear, and the absence of data 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. Triamterene has been shown to appear in animal milk, and this may also occur in humans. Additionally, thiazides are excreted in human breast milk. If the use of the combination drug product is deemed essential, lactating mothers should 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 developing hyperkalemia is heightened in patients taking potassium-sparing diuretics, particularly in those 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 frequently. Additionally, potassium-conserving therapies should be avoided in severely ill patients who may experience respiratory or metabolic acidosis. Regular 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 such situations is the potential for fluid and electrolyte imbalances.

Excessive doses of the triamterene component may lead to hyperkalemia, dehydration, nausea, vomiting, and weakness, with a risk of hypotension. Conversely, overdosing on hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, and lethargy, which may progress to coma, as well as gastrointestinal irritation.

Management of overdosage is primarily symptomatic and supportive. It is recommended that therapy with triamterene and hydrochlorothiazide be discontinued immediately. Healthcare professionals should consider inducing emesis or performing gastric lavage to mitigate the effects of the overdose.

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

Nonclinical Toxicology

Animal reproduction studies to evaluate the potential for fetal harm associated with triamterene and hydrochlorothiazide have not been conducted. A one-generation study in rats utilized a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day) and demonstrated no evidence of teratogenicity at doses that were 15 and 30 times the Maximum Recommended Human Dose (MRHD) based on body weight, and 3.1 and 6.2 times the MRHD based on body-surface area. However, 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 agents should only be used during pregnancy if the potential benefits justify the risks to the fetus.

Reproduction studies in rats have been conducted at doses up to 20 times the MRHD based on body weight and 6 times the MRHD based on body-surface area, with no evidence of fetal harm attributed to 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 correspond to multiples of the MRHD of 3000 for mice and 1000 for rats based on body weight, and 282 for mice and 206 for rats based on body-surface area, no evidence of fetal harm was observed. Nonetheless, there are no adequate and well-controlled studies in pregnant women.

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

Long-term studies involving triamterene and hydrochlorothiazide tablets have not been conducted. In studies overseen by the National Toxicology Program, rats were fed diets containing 0, 150, 300, or 600 ppm triamterene, while mice received diets containing 0, 100, 200, or 400 ppm triamterene. Male and female rats at the highest concentration received approximately 25 and 30 mg/kg/day, respectively, while male and female mice received approximately 45 and 60 mg/kg/day, respectively. An increased incidence of hepatocellular neoplasia, primarily adenomas, was noted in male and female mice at the highest dosage level. These doses represent 7.5 times and 10 times the MRHD of 300 mg/kg 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 the rat study was limited to triamterene-exposed males, with no statistically significant difference from control incidence at any dose level.

Two-year feeding studies in mice and rats, also conducted under the National Toxicology Program, administered hydrochlorothiazide at doses up to 600 mg/kg/day in mice and 100 mg/kg/day in rats. These doses correspond to 600 times (in mice) and 100 times (in rats) the MRHD for hydrochlorothiazide (50 mg/day or 1 mg/kg/day based on a 50 kg patient) on a body-weight basis, and 56 times (in mice) and 21 times (in rats) on a body-surface area basis. These studies revealed no evidence of carcinogenic potential for hydrochlorothiazide in rats or female mice, although 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 bacterial assays (S. typhimurium strains TA 98, TA 100, TA 1535, or TA 1537) with or without metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro, although it did induce sister chromatid exchanges in CHO cells under both conditions. Hydrochlorothiazide was not genotoxic in various in vitro assays, including the Ames test and tests for chromosomal aberrations in CHO cells, nor in in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. However, positive results were obtained in the in vitro CHO sister chromatid exchange test and mouse lymphoma cell mutagenicity assays at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans nondisjunction assay.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species 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 MRHD are 100 (mice) and 4 (rats) based on body weight, and 9.4 (mice) and 0.8 (rats) based on body-surface area.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicate that this increased risk is most pronounced in white patients who have received large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients who have taken a cumulative dose of 50,000 mg or more show a significantly higher risk, with an estimated 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 seeking shade when outdoors. Additionally, it is important for healthcare providers to emphasize the necessity of regular skin cancer screenings for patients on this medication, as they may be at an increased risk. Patients should be 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.

Additional Clinical Information

Clinicians should perform regular determinations of serum electrolytes to monitor for potential electrolyte imbalances in patients, particularly at appropriate intervals. Frequent serum and urine electrolyte assessments are crucial for patients experiencing vomiting or receiving parenteral fluids. Additionally, periodic measurements of blood urea nitrogen (BUN) and creatinine levels are recommended, especially for elderly patients or those with suspected or confirmed hepatic or renal impairments.

Patients prescribed hydrochlorothiazide should be counseled to protect their skin from sun exposure and to participate in regular skin cancer screenings. It is important to note that hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from the Sentinel System indicate that the risk is notably higher in white patients receiving large cumulative doses, with an estimated increase of approximately one additional SCC case per 16,000 patients per year in the general population, and one additional case for every 6,700 patients per year among those taking a cumulative dose of 50,000 mg or more.

FDA Insert (PDF)

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

View full prescribing information (PDF)