Triamterene/Hydrochlorothiazide

Description

Each triamterene and hydrochlorothiazide capsule, USP for oral use contains triamterene, USP 37.5 mg and hydrochlorothiazide, USP 25 mg. Hydrochlorothiazide, USP is slightly soluble in water and soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide, while it is sparingly soluble in methanol. The chemical structure of hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74 g/mol. At 50°C, triamterene, USP is practically insoluble in water (less than 0.1%) and is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in alcohol. Triamterene, USP is identified as 2,4,7-triamino-6-phenylpteridine, with a molecular formula of C12H11N7 and a molecular weight of 253.26 g/mol. Inactive ingredients include lactose monohydrate, pregelatinized starch, sodium starch glycolate, polysorbate 80, citric acid anhydrous, povidone, and magnesium stearate. The capsule shell is composed of titanium dioxide and gelatin. The capsule imprinting ink contains shellac glaze in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, ethanol, methanol, FD&C Blue # 2 Aluminum Lake, FD&C Red # 40 Aluminum Lake, FD&C Blue # 1 Aluminum Lake, and D&C Yellow # 10 Aluminum Lake.

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. Triamterene and hydrochlorothiazide capsules may be used alone or as an adjunct to other antihypertensive medications, such as beta-blockers; however, dosage adjustments may be necessary due to the potential enhancement of these agents' effects.

Limitations of use include that this drug is not indicated for the initial therapy of edema or hypertension, except in individuals where the risk of developing hypokalemia is unacceptable.

The routine use of diuretics in otherwise healthy pregnant women is inappropriate, as it exposes both the mother and fetus to unnecessary risks. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating established toxemia.

Diuretics may be indicated during pregnancy when edema is due to pathological causes, similar to their use in non-pregnant individuals. However, dependent edema resulting from the physiological and mechanical effects of pregnancy should be managed through non-pharmacological means, such as elevating the lower extremities and using support hose. The hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, and in cases where edema causes discomfort, increased recumbency is often sufficient for relief. In rare instances of extreme discomfort not alleviated by rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dose of triamterene and hydrochlorothiazide capsules is 1 or 2 capsules administered once daily. Healthcare professionals are advised to monitor serum potassium levels and assess the clinical effect regularly to ensure patient safety and therapeutic efficacy.

Contraindications

Triamterene and hydrochlorothiazide capsules are contraindicated in the following situations:

• The use of these capsules is contraindicated in patients receiving other potassium-sparing agents, such as spironolactone or amiloride, as well as other formulations containing triamterene. Concomitant use of potassium-containing salt substitutes is also prohibited due to the risk of hyperkalemia.

• Potassium supplementation is contraindicated except in severe cases of hypokalemia, as it may lead to rapid increases in serum potassium levels. If potassium supplementation is deemed necessary, careful monitoring of serum potassium levels is required.

• These capsules are contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the potential for exacerbating renal function.

• Hypersensitivity to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs is a contraindication for use.

• The capsules should not be administered to patients with pre-existing elevated serum potassium levels, as this may further increase the risk of hyperkalemia.

Warnings and Precautions

Caution is advised when administering triamterene and hydrochlorothiazide capsules to patients with diabetes, as thiazides may induce hyperglycemia, glycosuria, and modify insulin requirements. Additionally, diabetes mellitus may manifest during thiazide therapy.

Thiazides should be used judiciously in patients with impaired hepatic function, as they can precipitate hepatic coma in individuals with severe liver disease. The potassium depletion associated with thiazide use may exacerbate this risk. Healthcare professionals should monitor for early signs of impending hepatic coma, including confusion, drowsiness, and tremor. If mental confusion escalates, it is recommended to discontinue triamterene and hydrochlorothiazide capsules for a few days.

Electrolyte imbalances, which are frequently encountered in conditions such as heart failure, renal disease, or cirrhosis, may be exacerbated by diuretics. This consideration is particularly important during therapy with triamterene and hydrochlorothiazide capsules, especially when high doses are used for extended periods or in patients adhering to a salt-restricted diet. Caution is also warranted in patients with a history of renal stones.

In cases of serious hypokalemia, defined as serum potassium levels below 3.0 mEq/L, triamterene and hydrochlorothiazide capsules should be discontinued, and potassium chloride supplementation should be initiated. For less severe hypokalemia, evaluation of other coexisting conditions is necessary, and treatment should be adjusted accordingly. Warning signs of potential fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal symptoms.

Frequent monitoring of serum potassium levels is essential, particularly in patients receiving digitalis or those with a history of cardiac arrhythmias. Persistent potassium levels above 6 mEq/L necessitate careful observation and treatment, with immediate discontinuation of corrective measures for hypokalemia if laboratory results indicate an abnormal elevation of serum potassium.

Periodic assessments of serum creatinine and blood urea nitrogen (BUN) should be conducted, especially in elderly patients and those with suspected or confirmed renal insufficiency. If azotemia increases, triamterene and hydrochlorothiazide capsules should be discontinued. Furthermore, thiazides should be halted prior to conducting tests for parathyroid function to ensure accurate results.

Side Effects

Adverse reactions associated with the use of this medication have been observed across various systems, with some reactions categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, as well as severe dermatological conditions like erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis. Cardiovascular events such as arrhythmia and postural hypotension have also been reported. Renal complications, including acute renal failure (with one case noted as irreversible), interstitial nephritis, and renal stones primarily composed of triamterene, are significant concerns. Hematologic issues such as aplastic anemia, agranulocytosis, and hemolytic anemia have been documented, alongside leukopenia and thrombocytopenia with purpura.

Common adverse reactions include gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation, and abdominal pain, as well as jaundice and liver enzyme abnormalities. Metabolic changes, including diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia, have been frequently observed. Central nervous system effects, including weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo, are also prevalent. Musculoskeletal complaints, particularly muscle cramps, have been reported.

Miscellaneous reactions include impotence and sialadenitis. Respiratory issues such as allergic pneumonitis, pulmonary edema, and respiratory distress have been noted. In neonates and infants, rare occurrences of thrombocytopenia and pancreatitis have been reported in newborns whose mothers received thiazides during pregnancy.

Postmarketing experience has indicated an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients taking large cumulative doses of hydrochlorothiazide. The overall risk for SCC in the general population is approximately one 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 one additional case for every 6,700 patients per year.

Healthcare professionals should monitor patients for these adverse reactions and consider the risk factors associated with their use.

Drug Interactions

Potassium-sparing agents should be used with caution when administered alongside angiotensin-converting enzyme (ACE) inhibitors due to an elevated risk of hyperkalemia. Monitoring of serum potassium levels is recommended in patients receiving this combination.

The concurrent use of hydrochlorothiazide with amphotericin B or corticosteroids may exacerbate electrolyte imbalances, particularly leading to hypokalemia. Close monitoring of electrolyte levels is advised in patients receiving these combinations.

Oral anticoagulants may exhibit reduced efficacy when used in conjunction with hydrochlorothiazide. It may be necessary to adjust the dosage of the anticoagulant to maintain therapeutic effectiveness.

Triamterene and hydrochlorothiazide capsules can elevate blood uric acid levels, potentially necessitating dosage adjustments of antigout medications to effectively manage hyperuricemia and prevent gout attacks.

Due to the similar fluorescence spectra of triamterene and quinidine, the use of triamterene and hydrochlorothiazide capsules may interfere with the fluorescent measurement of quinidine, which could lead to inaccurate monitoring of quinidine levels.

The combination of triamterene with chlorpropamide may heighten the risk of severe hyponatremia. Patients should be monitored closely for signs of sodium depletion.

Additionally, there have been reports of acute renal failure in patients taking triamterene and hydrochlorothiazide capsules who are also treated with indomethacin. Caution is advised when considering this combination, and renal function should be monitored.

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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider this lack of established safety and efficacy when making treatment decisions for pediatric patients.

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 capsules, 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 indicated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced in elderly patients, leading to increased plasma levels following administration of triamterene and hydrochlorothiazide capsules.

To ensure patient safety, periodic assessments of blood urea nitrogen (BUN) or serum creatinine levels should be conducted, especially in elderly patients and those with suspected or confirmed renal insufficiency. These precautions are critical for the effective management of therapy in geriatric patients.

Pregnancy

The safe use of triamterene and hydrochlorothiazide capsules during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women. These capsules should only be administered during pregnancy if the potential benefits justify the risks to the fetus. It is important to note that animal reproduction studies may not always predict human responses; therefore, the use of this medication should be considered only when clearly necessary.

Both thiazides and triamterene have been shown to cross the placental barrier and can be detected in cord blood. Consequently, the use of these agents in pregnant patients necessitates a careful evaluation of the anticipated benefits against the potential hazards to the fetus. Possible risks associated with the use of thiazides and triamterene during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been observed in adults. Additionally, there are no adequate and well-controlled studies available for hydrochlorothiazide in pregnant women, further emphasizing the need for caution in prescribing these medications during pregnancy.

Lactation

Triamterene and thiazides in combination have not been studied in lactating mothers. However, triamterene has been shown to appear 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 this combination drug product is deemed essential, it is recommended that the lactating mother discontinue breastfeeding.

Renal Impairment

Triamterene and hydrochlorothiazide capsules are contraindicated in patients with anuria, acute and chronic renal insufficiency, or significant renal impairment. In patients with reduced kidney function, hyperkalemia is more likely to occur, particularly in those with diabetes (even in the absence of renal impairment), the elderly, or severely ill individuals.

Serum potassium levels must be monitored at frequent intervals, especially in patients initiating treatment with triamterene and hydrochlorothiazide capsules, when dosages are adjusted, or during any illness that may affect renal function. For patients with mild renal functional impairment, the use of this medication should be accompanied by frequent and ongoing monitoring of serum electrolytes.

Cumulative drug effects may be observed in patients with impaired renal function, as the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene have been shown to be reduced, leading to increased plasma levels in elderly patients and those with renal impairment.

Elevated serum creatinine and blood urea nitrogen (BUN) levels may occur due to a reversible reduction in glomerular filtration rate or depletion of intravascular fluid volume (prerenal azotemia), rather than indicating renal toxicity; these levels typically return to normal upon discontinuation of the medication. Periodic determinations of BUN or serum creatinine should be conducted, particularly in elderly patients and those with suspected or confirmed renal insufficiency. If azotemia increases, triamterene and hydrochlorothiazide capsules should be discontinued.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution, as these medications can precipitate hepatic coma in individuals with severe liver disease. When administering triamterene and hydrochlorothiazide capsules, healthcare providers must remain vigilant for early signs of impending coma, which may include confusion, drowsiness, and tremor. If there is an increase in mental confusion, it is recommended to discontinue the use of triamterene and hydrochlorothiazide capsules for a few days.

Additionally, attention must be given to other factors that could precipitate hepatic coma, such as the presence of blood in the gastrointestinal tract or pre-existing potassium depletion. Monitoring for these conditions is essential to ensure patient safety and to mitigate the risk of serious complications associated with hepatic impairment.

Overdosage

In cases of overdosage, electrolyte imbalance is the primary concern. Healthcare professionals should be vigilant for symptoms that may arise, which include polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes.

Reversible acute renal failure has been documented following the ingestion of 50 tablets of a formulation containing 50 mg of triamterene and 25 mg of hydrochlorothiazide. This highlights the potential severity of overdosage and the need for prompt medical intervention.

While triamterene is predominantly protein-bound (approximately 67%), there may still be a therapeutic advantage to employing dialysis in cases of significant overdosage. Healthcare providers are advised to assess the clinical situation and consider dialysis as a management option when appropriate.

Overall, immediate medical evaluation and supportive care are essential in managing overdosage to mitigate the risks associated with electrolyte disturbances and renal impairment.

Nonclinical Toxicology

Animal reproduction studies to assess the potential for fetal harm associated with triamterene and hydrochlorothiazide capsules have not been conducted. A one-generation study in rats, utilizing a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day), demonstrated no evidence of teratogenicity at these doses, which correspond to 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. The safe use of triamterene and hydrochlorothiazide capsules during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women.

Reproduction studies involving triamterene in rats at doses up to 20 times the MRHD based on body weight and 6 times the human dose based on body surface area revealed no evidence of fetal harm. Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses reaching 3,000 mg/kg/day for mice and 1,000 mg/kg/day for rats. These doses, which are multiples of the MRHD, also showed no evidence of fetal harm.

Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of these agents 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 capsules, either as a combination or individually, have not been conducted. Hydrochlorothiazide was subjected to two-year feeding studies in mice and rats, with 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, and 56 times and 21 times the MRHD based on body surface area. These studies did not reveal evidence of carcinogenic potential in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice.

Studies assessing the mutagenic potential of triamterene and hydrochlorothiazide capsules or triamterene alone have not been performed. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test and tests for chromosomal aberrations. However, positive results were observed in the in vitro CHO Sister Chromatid Exchange test and in mouse lymphoma cell assays at specific concentrations. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay.

Studies investigating the effects of triamterene and hydrochlorothiazide capsules or triamterene alone on animal reproductive function have not been conducted. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these animals were exposed to doses of up to 100 mg/kg/day for mice and 4 mg/kg/day for rats prior to mating and throughout gestation. These doses correspond to multiples of the MRHD of 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.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, as reported in postmarketing surveillance. Data from a study conducted within the Sentinel System indicate that the elevated risk is primarily linked to squamous cell carcinoma (SCC), particularly among white patients receiving large cumulative doses of the medication. The overall population exhibits an approximate risk increase of one 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 one 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 20° to 25°C (68° to 77°F), 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

Serum potassium levels should be monitored in patients taking triamterene and hydrochlorothiazide capsules, with a normal adult range of 3.5 to 5.0 mEq/L. If hypokalemia occurs, potassium supplementation or dietary adjustments are recommended, with careful monitoring of serum potassium levels. Persistent elevations above 6 mEq/L necessitate close observation and treatment. Clinicians should be aware that serum potassium levels may not accurately reflect total body potassium, and a rise in plasma pH can affect potassium concentrations. If serum potassium levels rise abnormally, corrective measures should be halted, and the medication should be discontinued until levels normalize.

Additionally, triamterene and hydrochlorothiazide capsules may lead to elevated blood urea nitrogen (BUN) and creatinine levels due to reversible reductions in glomerular filtration rate or intravascular fluid volume depletion. These levels typically normalize upon discontinuation of the medication. Regular monitoring of BUN and serum creatinine is advised, particularly in elderly patients or those with renal insufficiency. Thiazides can also lower serum protein-bound iodine levels without causing thyroid dysfunction, and they should be stopped prior to parathyroid function tests due to their effect on calcium excretion. While some patients on prolonged thiazide therapy have shown pathologic changes in parathyroid glands, common complications of hyperparathyroidism have not been observed.

FDA Insert (PDF)

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

View full prescribing information (PDF)