Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide tablets, USP combine triamterene USP, a potassium-conserving diuretic, with the natriuretic agent, hydrochlorothiazide, USP. Each triamterene and hydrochlorothiazide tablet USP is available in two strengths: 75 mg/50 mg, containing 75 mg of triamterene USP and 50 mg of hydrochlorothiazide USP, and 37.5 mg/25 mg, containing 37.5 mg of triamterene USP and 25 mg of hydrochlorothiazide USP. Both strengths are formulated for oral administration and contain the following inactive ingredients: anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrilin potassium, polyethylene glycol 8000, and povidone.

Triamterene, USP is chemically designated 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, soluble in formic acid, and sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol, and dilute mineral acids.

Hydrochlorothiazide, USP 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. It is slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

Uses and Indications

Triamterene and hydrochlorothiazide tablets are indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide alone. This combination is also indicated for patients requiring a thiazide diuretic in whom the risk of hypokalemia must be avoided, such as those on concomitant digitalis preparations or with a history of cardiac arrhythmias.

These tablets may be administered alone or in conjunction with other antihypertensive agents, including beta-blockers. It is important to note that triamterene and hydrochlorothiazide may enhance the effects of these medications, necessitating potential dosage adjustments.

Limitations of use include the routine use of diuretics in otherwise healthy pregnant women, which is deemed inappropriate and poses unnecessary risks to both mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there sufficient evidence supporting their efficacy in treating established toxemia.

In cases of edema during pregnancy, thiazides may be indicated when the edema is due to pathological causes, similar to their use in non-pregnant patients. However, dependent edema resulting from the 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 typically not harmful and is often accompanied by edema in many pregnant women. If this edema causes discomfort, increased recumbency may provide relief. In rare instances where extreme discomfort persists despite rest, a short course of diuretics may be considered appropriate.

Dosage and Administration

The usual dosage of triamterene and hydrochlorothiazide 37.5 mg/25 mg is one or two tablets administered once daily. It is essential to monitor serum potassium levels during treatment. For patients prescribed triamterene and hydrochlorothiazide 75 mg/50 mg, the recommended dosage is one tablet daily, also with appropriate monitoring of serum potassium.

There is no clinical experience supporting the use of more than one 75 mg/50 mg tablet daily or more than two 37.5 mg/25 mg tablets daily. In cases where patients require hydrochlorothiazide therapy but cannot tolerate the risk of hypokalemia, treatment may be initiated with the 37.5 mg/25 mg formulation.

If an optimal blood pressure response is not achieved with the initial dose of 37.5 mg/25 mg, the dosage may be increased to either two 37.5 mg/25 mg tablets daily as a single dose or one 75 mg/50 mg tablet daily.

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. If hyperkalemia develops, the medication should be discontinued, and a thiazide alone should be substituted.

The combination should not be administered to patients receiving other potassium-conserving agents, such as spironolactone or amiloride hydrochloride, or other formulations containing triamterene. Concomitant potassium supplementation, including medications, potassium-containing salt substitutes, or potassium-enriched diets, is also contraindicated.

This medication is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the potential for exacerbating renal function.

Additionally, triamterene and hydrochlorothiazide should not be used in patients with a known hypersensitivity to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs.

Warnings and Precautions

Patients receiving triamterene and hydrochlorothiazide are at risk for hyperkalemia, characterized by serum potassium levels of 5.5 mEq/liter or greater. This condition is particularly prevalent in individuals with renal impairment, diabetes (regardless of renal function), the elderly, or those who are severely ill. Due to the potential fatality of uncorrected hyperkalemia, it is imperative that serum potassium levels be monitored frequently, especially during the initiation of therapy, following dosage adjustments, or in the presence of any illness that may affect renal function.

In cases where hyperkalemia is suspected—indicated by symptoms such as paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, or shock—an electrocardiogram (ECG) should be performed. It is crucial to note that mild hyperkalemia may not present with ECG changes, thus ongoing monitoring of serum potassium levels is essential. Should hyperkalemia be confirmed, triamterene and hydrochlorothiazide must be discontinued immediately, and a thiazide diuretic should be substituted. If serum potassium levels exceed 6.5 mEq/liter, more aggressive treatment is warranted, which may include intravenous calcium chloride, sodium bicarbonate, and/or glucose with rapid-acting insulin. Cationic exchange resins, such as sodium polystyrene sulfonate, may also be administered orally or rectally, and persistent hyperkalemia may necessitate dialysis.

The risk of hyperkalemia is heightened in patients with renal impairment. Therefore, individuals with mild renal functional impairment should not be prescribed this combination without close and continuous monitoring of serum electrolytes, as cumulative drug effects may occur. Additionally, hyperkalemia has been documented in diabetic patients using potassium-sparing agents, even in the absence of renal impairment. Consequently, triamterene and hydrochlorothiazide should be avoided in diabetic patients unless serum electrolytes can be monitored frequently. Caution is also advised when co-administering these agents with angiotensin-converting enzyme (ACE) inhibitors due to their potassium-sparing effects.

General precautions include vigilant monitoring for fluid and electrolyte imbalances, such as hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Serum electrolyte determinations should be conducted at appropriate intervals, particularly in patients experiencing vomiting or receiving parenteral fluids. Triamterene and hydrochlorothiazide may elevate blood urea nitrogen (BUN) and creatinine levels; therefore, periodic assessments of these parameters are recommended, especially in elderly patients or those with suspected hepatic or renal insufficiencies. If azotemia worsens, discontinuation of the medication is advised.

Caution is warranted in patients with impaired hepatic function or progressive liver disease, as even minor fluid and electrolyte imbalances could precipitate hepatic coma. Additionally, triamterene has been associated with renal stones in conjunction with other calculus components, necessitating careful use in patients with a history of renal lithiasis. As a weak folic acid antagonist, triamterene may contribute to megaloblastosis in patients with diminished folic acid stores; thus, periodic blood evaluations are recommended in these cases. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazide therapy.

Sensitivity reactions to thiazides can occur in patients with or without a history of allergy or bronchial asthma, and there have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use.

In summary, healthcare professionals must ensure rigorous monitoring of serum potassium levels, electrolytes, BUN, and creatinine, particularly in at-risk populations. Immediate medical intervention is required if hyperkalemia is suspected, and appropriate adjustments to therapy should be made based on clinical findings.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, which can be categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, as well as hematologic conditions like agranulocytosis, thrombocytopenia, and aplastic anemia. Additionally, acute renal failure and acute interstitial nephritis have been reported. Patients may also experience severe gastrointestinal reactions, including intrahepatic cholestatic jaundice and pancreatitis. It is important to note that hyperkalemia, defined as an abnormal elevation of serum potassium levels (≥5.5 mEq/liter), can occur, particularly in patients with renal impairment, diabetes, or those who are elderly or severely ill. Uncorrected hyperkalemia may be fatal.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal symptoms such as nausea, vomiting, diarrhea, constipation, and appetite disturbance. Central nervous system effects such as drowsiness, fatigue, insomnia, headache, and dizziness are also frequently observed. Cardiovascular reactions may include tachycardia and shortness of breath, with potential chest pain and orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, or narcotics.

Other notable adverse reactions encompass renal issues, including urine discoloration and the formation of renal stones composed of triamterene. Hematologic changes such as leukopenia and megaloblastosis have also been documented. Ophthalmic effects may include xanthopsia and transient blurred vision.

Patients may report hypersensitivity reactions such as rash, urticaria, and photosensitivity, along with systemic symptoms like fever and respiratory distress, including pneumonitis. Additional adverse reactions may involve muscle cramps, weakness, decreased sexual performance, and sialadenitis.

Altered laboratory findings have been observed, including hyperkalemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremia. Reversible elevations in blood urea nitrogen (BUN) and serum creatinine levels have also been noted, alongside hyperglycemia and glycosuria, which may lead to diabetes mellitus. Elevated liver enzymes have been reported as well.

In postmarketing experience, there is 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.

Whenever adverse reactions are moderate to severe, it is recommended that therapy be reduced or withdrawn to mitigate risks to patient health.

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.

In addition, thiazides can diminish the arterial responsiveness to norepinephrine; however, they do not negate the effectiveness of pressor agents. This interaction should be considered when managing patients who require both thiazide therapy and norepinephrine.

Lithium administration is contraindicated with diuretics, including thiazides, due to the potential for reduced renal clearance of lithium, which significantly increases the risk of lithium toxicity. Regular monitoring of lithium levels is recommended for patients who may require both therapies.

The combination of indomethacin with triamterene and hydrochlorothiazide has been associated with reports of acute renal failure. Caution is warranted when considering this combination, and renal function should be monitored closely.

Potassium-sparing diuretics, such as triamterene, should be used with caution in conjunction with ACE inhibitors due to the heightened risk of hyperkalemia. Frequent monitoring of serum potassium levels is advised to prevent potential complications.

Lastly, triamterene and quinidine share similar fluorescence spectra, which may lead to interference in quinidine measurement when triamterene and hydrochlorothiazide are co-administered. Clinicians should be aware of this potential interaction when interpreting quinidine levels in patients receiving these medications.

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 may experience an increased risk of hyperkalemia when treated with this medication. It is essential to monitor serum potassium levels at frequent intervals, particularly in elderly patients who are initiating therapy with triamterene and hydrochlorothiazide, when dosages are adjusted, or during any illness that may affect renal function.

Clinical findings indicate 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 compounds. Therefore, careful consideration should be given to dose adjustments in this population.

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 safety and efficacy of treatment in geriatric patients.

Pregnancy

The use of triamterene and hydrochlorothiazide tablets during pregnancy has not been established as safe, as there are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted to determine the potential for fetal harm specifically associated with these tablets. However, reproduction studies involving triamterene 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 show evidence of harm to the fetus. Similarly, hydrochlorothiazide has been administered to pregnant mice and rats during critical periods of organogenesis at doses up to 3,000 mg/kg/day and 1,000 mg/kg/day, respectively, without evidence of fetal harm.

Despite these findings in animal studies, it is important to note that such studies are not always predictive of human response. Therefore, triamterene and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefits justify the risks to the fetus. The anticipated benefits must be carefully weighed against possible hazards, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been observed in adults. Additionally, both thiazides and triamterene have been shown to cross the placental barrier and can appear in cord blood, further necessitating caution in their use during pregnancy.

Lactation

Thiazides and triamterene in combination have not been studied in nursing mothers. However, triamterene has been shown to appear in animal milk, suggesting that it may also be excreted in human breast milk. Additionally, thiazides are known to be excreted in human breast milk.

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.

For patients with mild renal functional impairment, the use of this medication is not recommended without ongoing and frequent 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.

In diabetic patients, hyperkalemia has been reported with the use of potassium-conserving agents, even in the absence of apparent renal impairment; therefore, triamterene and hydrochlorothiazide should be avoided in this population. If these agents are used in severely ill patients, it is crucial to avoid potassium-conserving therapy, particularly in cases where respiratory or metabolic acidosis may develop, as this condition can lead to rapid increases in serum potassium levels. Frequent evaluations of acid/base balance and serum electrolytes are essential in these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. Consequently, there is no available information regarding dosage adjustments, special monitoring requirements, or precautions 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 warranted based on clinical judgment.

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, overdosing 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

Studies evaluating the teratogenic effects of the combination of triamterene and hydrochlorothiazide, as well as triamterene alone, on animal reproductive function have not been conducted. However, hydrochlorothiazide did not demonstrate adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed to dietary 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 Maximum Recommended Human Dose (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.

Long-term studies involving the triamterene and hydrochlorothiazide combination have not been performed. In studies conducted under the auspices of the National Toxicology Program, groups of rats were administered diets containing 0, 150, 300, or 600 ppm triamterene, while groups of mice received diets containing 0, 100, 200, or 400 ppm triamterene. Male and female rats exposed to 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 observed in male and female mice at the highest dosage level, which represents 7.5 times and 10 times the MRHD of 300 mg/kg (or 6 mg/kg/day based on a 50 kg patient) for male and female mice, respectively, when calculated based on body weight, and 0.7 times and 0.9 times the MRHD when based on body surface area. In contrast, hepatocellular neoplasia in the rat study was limited to triamterene-exposed males, with no dose-dependent relationship and no statistically significant difference from control incidence at any dose level.

Two-year feeding studies in mice and rats, also conducted under the auspices of the National Toxicology Program, evaluated doses of hydrochlorothiazide up to 600 mg/kg/day for mice and 100 mg/kg/day for rats. These doses correspond to 600 times (in mice) and 100 times (in rats) the MRHD for the hydrochlorothiazide component of triamterene and hydrochlorothiazide tablets (50 mg/day or 1 mg/kg/day based on a 50 kg patient). Based on body surface area, these doses are 56 times (in mice) and 21 times (in rats) the MRHD. The studies found no evidence of carcinogenic potential for hydrochlorothiazide in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

Studies assessing the mutagenic potential of the triamterene and hydrochlorothiazide combination have not been performed. Triamterene was not found to be mutagenic in bacterial strains (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, regardless of metabolic activation, but it did induce sister chromatid exchanges in CHO cells in vitro with and without metabolic activation. Hydrochlorothiazide was not genotoxic in in vitro assays using various strains of Salmonella typhimurium (the Ames test), in the CHO test for chromosomal aberrations, or in in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were observed in the in vitro CHO sister chromatid exchange (clastogenicity) test and in mouse lymphoma cell (mutagenicity) assays at hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL. Additionally, positive results were obtained in the Aspergillus nidulans nondisjunction assay using an unspecified concentration of hydrochlorothiazide.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data derived from a study conducted within the Sentinel System indicate that this increased risk is notably observed 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 demonstrate a heightened risk, with an estimated 1 additional case of SCC occurring 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

Clinicians should conduct laboratory tests to monitor serum electrolytes at appropriate intervals to detect potential imbalances, particularly in patients experiencing vomiting or receiving parenteral fluids. Regular assessments of serum and urine electrolytes are crucial, along with periodic blood urea nitrogen (BUN) and creatinine tests, especially in elderly patients or those with suspected hepatic or renal insufficiencies.

Patient counseling should include awareness of warning signs of fluid and electrolyte imbalance, such as dryness of mouth, thirst, weakness, and gastrointestinal disturbances. In cases of actual salt depletion, appropriate replacement therapy is essential. Clinicians should note that hypokalemia may heighten the heart's sensitivity to digitalis toxicity, and triamterene, a weak folic acid antagonist, may lead to megaloblastosis in patients with diminished folic acid stores, necessitating periodic blood evaluations. Additionally, thiazide therapy may cause hyperuricemia or precipitate acute gout, and should be paused prior to parathyroid function tests. Insulin requirements in diabetic patients may vary, and sensitivity reactions to thiazides can occur regardless of prior allergy history. There have also been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use.

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)