Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide is a combination medication that includes triamterene, a potassium-conserving diuretic, and hydrochlorothiazide, a natriuretic agent. The formulation is available in two tablet strengths: each Triamterene and Hydrochlorothiazide 37.5 mg/25 mg Tablet, USP contains 37.5 mg of triamterene, USP and 25 mg of hydrochlorothiazide, USP, while each Triamterene and Hydrochlorothiazide 75 mg/50 mg Tablet, USP contains 75 mg of triamterene, USP and 50 mg of hydrochlorothiazide, USP.

The tablets are intended for oral administration and contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 37.5 mg/25 mg tablets also include D&C Yellow No.10 Aluminum Lake and FD&C Blue No.1 Aluminum Lake.

Chemically, triamterene is identified as 2,4,7-triamino-6-phenylpteridine and is characterized by its practically insoluble nature in water, benzene, chloroform, ether, and dilute alkali hydroxides. It is soluble in formic acid and sparingly soluble in methoxyethanol, with very slight solubility in acetic acid, alcohol, and dilute mineral acids. Hydrochlorothiazide, on the other hand, is designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, exhibiting slight solubility in water and free solubility in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids, with a molecular weight of 297.73.

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 include the routine use of diuretics in otherwise healthy pregnant women, which 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.

While edema during pregnancy may arise from pathological causes or physiological changes, thiazides are indicated only when edema is due to pathological causes. Dependent edema resulting from venous return restriction by the expanded uterus should be managed through non-pharmacological means, such as elevation of the lower extremities and the use of support hose. In rare cases where edema causes extreme discomfort not relieved by rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dosage of Triamterene and Hydrochlorothiazide 37.5 mg/25 mg is one or two tablets administered daily 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 no clinical experience supporting the use of more than one 75 mg/50 mg tablet or more than two 37.5 mg/25 mg tablets in a single day. In patients requiring hydrochlorothiazide therapy who cannot tolerate hypokalemia, treatment may be initiated with the 37.5 mg/25 mg formulation of triamterene and hydrochlorothiazide.

If an optimal blood pressure response is not achieved with the 37.5 mg/25 mg dosage, the healthcare provider may consider increasing the dose to two 37.5 mg/25 mg tablets daily as a single dose or switching to one 75 mg/50 mg tablet daily.

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 triamterene/25 mg hydrochlorothiazide formulation.

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 37.5 mg/25 mg tablet of triamterene and hydrochlorothiazide 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. 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. Additionally, concomitant potassium supplementation, including medications, potassium-containing salt substitutes, or potassium-enriched diets, is contraindicated.

The use of triamterene and hydrochlorothiazide is also 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. Furthermore, 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

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), the elderly, or those who are severely ill. 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 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 administration of 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, and those with mild renal functional impairment should not be treated with this combination without continuous monitoring of serum electrolytes. Cumulative drug effects may occur in this population. Additionally, diabetic patients are at risk for hyperkalemia even without evident renal impairment; therefore, the use of triamterene and hydrochlorothiazide in this group should be approached with caution, and serum electrolytes should 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, patients with a history of renal lithiasis should be monitored closely. Triamterene acts as a weak folic acid antagonist and may lead to megaloblastosis in individuals 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 undergoing thiazide therapy.

In summary, healthcare professionals must ensure that serum potassium levels, serum electrolytes, and periodic BUN and creatinine levels are monitored diligently to mitigate the risks associated with triamterene and hydrochlorothiazide therapy. Immediate medical attention should be sought if hyperkalemia is suspected, and the medication should be discontinued if hyperkalemia or azotemia is confirmed.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, 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. Additionally, there is a noted risk of non-melanoma skin cancer, particularly squamous cell carcinoma, in white patients taking large cumulative doses of hydrochlorothiazide.

Common gastrointestinal adverse reactions include nausea, vomiting, diarrhea, constipation, and appetite disturbance. Patients may also experience jaundice, pancreatitis, gastric irritation, and cramping. Central nervous system effects such as drowsiness, fatigue, insomnia, headache, dizziness, and dry mouth are frequently reported. Psychological symptoms, including depression, anxiety, and restlessness, may also occur.

Cardiovascular reactions can manifest as tachycardia, shortness of breath, and chest pain, with orthostatic hypotension potentially exacerbated by alcohol, barbiturates, or narcotics. Renal-related adverse reactions may include urine discoloration and the formation of renal stones composed of triamterene.

Hematologic adverse reactions include leukopenia, hemolytic anemia, and megaloblastosis. Ophthalmic effects such as xanthopsia and transient blurred vision have been noted. Other 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 and serum creatinine levels have been reported, along with hyperglycemia, glycosuria, and diabetes mellitus. Elevated liver enzymes have also been documented.

Postmarketing experience has highlighted the association of hydrochlorothiazide with an increased risk of non-melanoma skin cancer, particularly in patients with significant cumulative exposure.

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 shown to increase responsiveness to neuromuscular blocking agents such as tubocurarine, which may necessitate adjustments in dosing or monitoring of neuromuscular function.

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 package insert for lithium prior to considering such combination therapy.

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

The use of potassium-sparing diuretics in conjunction with angiotensin-converting enzyme (ACE) inhibitors should be approached with extreme caution due to a markedly increased 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 this potential interaction when interpreting quinidine measurements.

Packaging & NDC

The table below lists all NDC Code configurations of Triamterene and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Elderly patients, particularly those aged 65 and older, are at an increased risk for hyperkalemia, especially if they have renal impairment or diabetes, even in the absence of renal impairment. It is essential to monitor serum potassium levels at frequent intervals in this population, particularly when initiating treatment with triamterene and hydrochlorothiazide, when dosages are adjusted, or during any illness that may affect renal function.

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, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, as elevations in these parameters may occur more frequently in geriatric patients.

Additionally, cumulative drug effects may be observed in elderly patients with impaired renal function, necessitating careful consideration of dosing and monitoring to mitigate potential adverse effects.

Pregnancy

The safe use of triamterene and hydrochlorothiazide during pregnancy has not been established, as there are no adequate and well-controlled studies in pregnant women. These medications should only be used during pregnancy if the potential benefits justify the risks to the fetus.

Both thiazides and triamterene have been shown to cross the placental barrier and can be detected in cord blood. Therefore, the anticipated benefits of treatment must be carefully weighed against potential hazards to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions observed in adults.

Animal reproduction studies have been conducted with hydrochlorothiazide in pregnant mice and rats during critical periods of organogenesis, with doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively, showing no evidence of fetal harm. However, due to the limitations of animal studies in predicting human outcomes, the use of this drug in pregnant patients should be considered only when clearly necessary.

Reproductive 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, have not demonstrated any harm to the fetus. Nonetheless, the absence of adequate human data necessitates caution in prescribing these medications to women of childbearing potential.

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

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 the renal clearances of hydrochlorothiazide and the active metabolite of triamterene are reduced, 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 generally be avoided in this population. 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 cases where triamterene and hydrochlorothiazide are administered to patients with acidosis, regular evaluations of acid/base balance and serum electrolytes are necessary.

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.

Clinical Manifestations The primary concern in overdosage is the potential for fluid and electrolyte imbalances. Excessive doses of triamterene may lead to hyperkalemia, dehydration, nausea, vomiting, weakness, and possibly hypotension. Conversely, overdosing on hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, lethargy (which may progress to coma), and gastrointestinal irritation.

Management Management of overdosage is 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 absorption of the drug. Continuous monitoring of serum electrolyte levels and fluid balance is essential to address any imbalances that may arise.

Supportive measures should be instituted as necessary to maintain hydration, electrolyte balance, and the proper functioning of respiratory, cardiovascular, and renal systems.

Nonclinical Toxicology

No teratogenic effects were observed in studies involving hydrochlorothiazide. In non-teratogenic assessments, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when administered via diet at 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 times for mice and 4 times for rats based on body weight, and 9.4 times for mice and 0.8 times for rats based on body surface area.

Long-term studies evaluating the triamterene and hydrochlorothiazide combination have not been conducted. In studies supported by the National Toxicology Program, rats were fed diets containing triamterene at concentrations of 0, 150, 300, or 600 ppm, while mice received 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 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, 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 based on body surface area. In contrast, hepatocellular neoplasia in rats 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 for mice and 100 mg/kg/day for rats. These doses correspond to 600 times the MRHD for hydrochlorothiazide in mice and 100 times in rats based on body weight, and 56 times in mice and 21 times in rats based on body surface area. 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 effects of triamterene and hydrochlorothiazide on animal reproductive function have not been performed. Additionally, investigations into the mutagenic potential of the triamterene and hydrochlorothiazide combination have not been conducted. Triamterene was found to be non-mutagenic in bacterial assays using S. typhimurium strains TA 98, TA 100, TA 1535, or TA 1537, both with and without metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro under similar conditions, but it did induce sister chromatid exchanges in CHO cells in vitro with and without metabolic activation. 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 in mouse lymphoma cell mutagenicity assays at concentrations ranging from 43 to 1300 mcg/mL. Positive results were also noted in the Aspergillus nidulans nondisjunction assay with hydrochlorothiazide at an unspecified concentration.

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 predominantly observed in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. Notably, for white patients receiving 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. These findings are based on voluntary reports and data collected through surveillance programs.

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 equipped with a child-resistant closure. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by 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 frequently in patients initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of any illness that may affect renal function. Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine are recommended, particularly for elderly patients and those with suspected or confirmed hepatic or renal impairments.

The standard dosing regimen for triamterene and hydrochlorothiazide 37.5 mg/25 mg is one or two tablets daily, administered as a single dose, while the 75 mg/50 mg formulation is typically prescribed as one tablet daily, both requiring appropriate monitoring of serum potassium. Patients should be counseled to protect their skin from sun exposure and to participate in regular skin cancer screenings, as hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) 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, escalating to one additional case for every 6,700 patients per year among white patients taking cumulative doses 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 Apotex Corp.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)