Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide tablets, USP are a combination of triamterene, a potassium-conserving diuretic, and hydrochlorothiazide, a natriuretic agent. These tablets are available in two strengths: 75 mg/50 mg and 37.5 mg/25 mg. Each 75 mg/50 mg tablet contains 75 mg of triamterene and 50 mg of hydrochlorothiazide, while each 37.5 mg/25 mg tablet contains 37.5 mg of triamterene and 25 mg of hydrochlorothiazide.

The inactive ingredients in both strengths include anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrilin potassium, polyethylene glycol 8000, and povidone. The 37.5 mg/25 mg strength also contains FD&C Blue No. 2 Aluminum Lake.

Triamterene, with a molecular weight of 253.27, is chemically defined as 2,4,7-triamino-6-phenylpteridine. It is practically insoluble in water, benzene, chloroform, ether, and dilute alkali hydroxides, but soluble in formic acid and sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol, and dilute mineral acids.

Hydrochlorothiazide, with a molecular weight of 297.73, is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. 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

Triamterene and hydrochlorothiazide tablets are indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide monotherapy. This combination is also indicated for patients requiring a thiazide diuretic where the risk of hypokalemia must be minimized, 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 potentiate the effects of these medications, necessitating potential dosage adjustments.

Limitations of Use: The routine use of diuretics in otherwise healthy pregnant women is not recommended, as it poses unnecessary risks to both the 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, which may arise from pathological causes or physiological changes, thiazides may be indicated when the edema is due to pathological conditions, similar to their use in non-pregnant patients. However, dependent edema resulting from venous return restriction due to an expanded uterus should be managed through non-pharmacological means, such as elevating the lower extremities and using support hose. The use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary.

During normal pregnancy, hypervolemia is common and typically does not harm the mother or fetus in the absence of cardiovascular disease, although it may be associated with generalized edema. 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 appropriate for symptom relief.

Dosage and Administration

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

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. Administration of two 37.5 mg/25 mg tablets daily in divided doses has been associated with an increased risk of electrolyte imbalance and renal dysfunction.

Patients currently receiving 50 mg of hydrochlorothiazide who develop hypokalemia may be transitioned directly to the 75 mg/50 mg formulation. Similarly, patients on 25 mg of hydrochlorothiazide who experience hypokalemia may be switched directly to the 37.5 mg/25 mg formulation. For patients requiring hydrochlorothiazide therapy where hypokalemia is a concern, treatment may be initiated with the 37.5 mg/25 mg formulation of triamterene and hydrochlorothiazide.

If optimal blood pressure control 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. 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, can be safely converted to one tablet of triamterene and hydrochlorothiazide 37.5 mg/25 mg 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.

Concomitant use with other potassium-conserving agents, such as spironolactone or amiloride hydrochloride, is contraindicated. Additionally, potassium supplementation in any form, including medications, potassium-containing salt substitutes, or potassium-enriched diets, should not be used.

This combination is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment, as these conditions may exacerbate renal function.

Hypersensitivity to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs also contraindicates the use of this medication.

Warnings and Precautions

Patients receiving triamterene and hydrochlorothiazide must be closely monitored for the potential development of hyperkalemia, characterized by serum potassium levels equal to or exceeding 5.5 mEq/liter. This condition is particularly prevalent in individuals with renal impairment, diabetes (even in the absence of renal dysfunction), and among elderly or severely ill patients. Due to the risk of fatal outcomes associated with uncorrected hyperkalemia, it is imperative that serum potassium levels are assessed at frequent intervals, especially when initiating therapy, adjusting dosages, or during 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 administration of calcium chloride, sodium bicarbonate, and/or glucose with rapid-acting insulin. Cationic exchange resins such as sodium polystyrene sulfonate may also be utilized, 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 rigorous and continuous monitoring of serum electrolytes, as cumulative drug effects may occur. Additionally, diabetic patients are at increased risk for hyperkalemia when using potassium-sparing agents, and triamterene and hydrochlorothiazide should be avoided in this population unless serum electrolytes can be closely monitored. 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. Symptoms indicative of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances.

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 increases, 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.

Patients with a history of renal lithiasis should use triamterene and hydrochlorothiazide with caution, as triamterene has been associated with the formation of renal stones. Additionally, due to its weak folic acid antagonistic properties, periodic blood evaluations are recommended for patients with diminished folic acid stores. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazide therapy. Sensitivity reactions to thiazides can occur in individuals with or without a prior history of allergy or bronchial asthma.

In summary, healthcare professionals must ensure that patients on triamterene and hydrochlorothiazide are monitored closely for potential adverse effects, particularly hyperkalemia and electrolyte imbalances, and that appropriate laboratory tests are conducted to mitigate risks associated with this medication.

Side Effects

Patients may experience a range of adverse reactions while using this medication, categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, respiratory distress including pneumonitis, and severe hematologic conditions like agranulocytosis and aplastic anemia. Additionally, patients may experience acute renal failure and acute interstitial nephritis. Hyperkalemia, characterized by an abnormal elevation of serum potassium levels, is a significant concern, particularly in patients with renal impairment, diabetes, or those who are elderly or severely ill. Uncorrected hyperkalemia can be fatal, necessitating frequent monitoring of serum potassium levels, especially when initiating treatment or adjusting dosages.

Common gastrointestinal adverse reactions reported include nausea, vomiting, diarrhea, constipation, and appetite disturbance. Other gastrointestinal effects may involve jaundice (intrahepatic cholestatic jaundice), pancreatitis, gastric irritation, cramping, and taste alteration. Central nervous system effects such as drowsiness, fatigue, insomnia, headache, dizziness, and dry mouth have also been observed. Patients may report mood-related symptoms, including depression and anxiety, as well as vertigo, restlessness, and paresthesias.

Cardiovascular reactions may include tachycardia, shortness of breath, chest pain, and orthostatic hypotension, which can be exacerbated by alcohol, barbiturates, or narcotics. Renal-related adverse reactions encompass urine discoloration and the formation of renal stones composed of triamterene in association with other calculus materials.

Hematologic reactions include leukopenia, thrombocytopenia, hemolytic anemia, and megaloblastosis. Ophthalmic effects such as xanthopsia and transient blurred vision have also been reported. Other adverse reactions may involve muscle cramps, weakness, decreased sexual performance, and sialadenitis.

Altered laboratory findings have been noted, including hyperkalemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremia. Reversible elevations in blood urea nitrogen (BUN) and serum creatinine levels have been observed in hypertensive patients treated with this medication. Additionally, hyperglycemia, glycosuria, and diabetes mellitus have been reported, along with elevated liver enzymes.

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 taking large cumulative doses. The risk for SCC in the overall 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.

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 have been observed to decrease arterial responsiveness to norepinephrine; however, this effect does not compromise the therapeutic efficacy of norepinephrine as a pressor agent. Additionally, thiazides may increase the responsiveness to neuromuscular blocking agents such as tubocurarine, necessitating careful 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, which significantly increases the risk of lithium toxicity. It is advisable to consult the package insert for lithium prior to considering this combination therapy.

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

The combination of potassium-sparing agents with angiotensin-converting enzyme (ACE) inhibitors should be approached with extreme caution due to the heightened risk of hyperkalemia. Frequent monitoring of serum potassium levels is essential to mitigate this risk.

Lastly, triamterene and quinidine share similar fluorescence spectra, which may interfere with the accurate measurement of quinidine levels when used concurrently with triamterene and hydrochlorothiazide. Clinicians should consider alternative monitoring strategies to ensure accurate assessment of quinidine concentrations.

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 the potential risks and benefits before prescribing this medication to 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 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 compounds. Therefore, careful consideration should be given to dose adjustments in this population to mitigate potential adverse effects.

Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, especially 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 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 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, also did not demonstrate 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 only be used during pregnancy 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 potentially other adverse reactions 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 (even in the absence of renal impairment), 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 drug 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, the use of potassium-conserving agents, including triamterene and hydrochlorothiazide, should be avoided due to the risk of hyperkalemia, which has been reported even in the absence of apparent renal impairment. If these agents are used in diabetic patients, frequent monitoring of serum electrolytes is essential.

Additionally, potassium-conserving therapy should be avoided in severely ill patients at risk for respiratory or metabolic acidosis, as acidosis can lead to rapid increases in serum potassium levels. In patients with acidosis receiving triamterene and hydrochlorothiazide, regular evaluations of acid/base balance and serum electrolytes are necessary to ensure patient safety.

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

Studies evaluating the teratogenic effects of the triamterene and hydrochlorothiazide combination, as well as triamterene alone, on animal reproductive function have not been conducted. However, hydrochlorothiazide demonstrated no adverse effects on the fertility of both male and female mice and rats when administered via diet at doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, 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 National Toxicology Program, rats were fed diets containing triamterene at concentrations of 0, 150, 300, or 600 ppm, while mice were fed diets with 0, 100, 200, or 400 ppm. 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, respectively. An increased incidence of hepatocellular neoplasia, primarily adenomas, was observed in male and female mice at the highest dosage level, representing 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 based on body surface area. In contrast, hepatocellular neoplasia in the rat study was limited to males exposed to triamterene, 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 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) when calculated on a body weight basis, and 56 times (in mice) and 21 times (in rats) based on body surface area. These 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 various strains of bacteria (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, but it did induce sister chromatid exchanges in CHO cells both with and without metabolic activation. Hydrochlorothiazide was not genotoxic in in vitro assays using multiple 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. However, positive results were obtained in the in vitro CHO sister chromatid exchange test and in mouse lymphoma cell assays at hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay using an unspecified concentration of hydrochlorothiazide.

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 encouraged to report any new or unusual skin changes 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 perform serum electrolyte determinations at appropriate intervals to detect potential electrolyte imbalances in patients. This is particularly crucial for those experiencing vomiting or receiving parenteral fluids, as frequent monitoring of serum and urine electrolytes is advised.

The usual dosing regimen for triamterene and hydrochlorothiazide 37.5 mg/25 mg is one or two tablets daily as a single dose, with careful monitoring of serum potassium levels. For the 75 mg/50 mg formulation, the recommended dose is one tablet daily, also with appropriate potassium monitoring. Patients prescribed hydrochlorothiazide should be counseled to protect their skin from sun exposure and to undergo regular skin cancer screenings. Notably, hydrochlorothiazide has been linked to 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 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 about 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 Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)