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 is 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

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

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

In cases of edema during pregnancy, thiazides may be indicated when the edema is due to pathological causes. 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 to the mother or fetus, provided there are no underlying cardiovascular issues. If discomfort arises from this edema and is not alleviated by increased recumbency, a short course of diuretics may be considered appropriate in rare instances.

Dosage and Administration

The usual dosage of triamterene and hydrochlorothiazide 37.5 mg/25 mg is one or two tablets administered once daily. Serum potassium levels should be monitored appropriately during treatment. For patients prescribed triamterene and hydrochlorothiazide 75 mg/50 mg, the recommended dosage is one tablet daily, with similar monitoring of serum potassium.

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 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 taken once daily or one 75 mg/50 mg tablet taken once 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, including spironolactone, amiloride hydrochloride, or other formulations containing triamterene. Concomitant potassium supplementation, whether through medication, 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.

• Use is contraindicated in patients with a known hypersensitivity to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs.

Warnings and Precautions

Patients receiving triamterene and hydrochlorothiazide must be closely monitored for the potential development of hyperkalemia, characterized by serum potassium levels of 5.5 mEq/liter or greater. 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 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 interventions are 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, and those with mild renal functional impairment should not be treated with this combination without rigorous and ongoing monitoring of serum electrolytes. Cumulative effects of the medication may be observed in this population. Additionally, diabetic patients are at increased risk for hyperkalemia when using potassium-sparing agents, and therefore, triamterene and hydrochlorothiazide should be avoided in these individuals unless serum electrolytes can be monitored closely. Caution is also advised when co-administering these agents with angiotensin-converting enzyme (ACE) inhibitors due to their potassium-sparing properties.

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; thus, 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. The use of triamterene and hydrochlorothiazide should also be approached with care in individuals with a history of renal lithiasis, as triamterene has been associated with the formation of renal stones. Furthermore, 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 occur in some patients receiving thiazide therapy. Sensitivity reactions to thiazides can manifest in patients regardless of prior allergy or bronchial asthma history.

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 regimen.

Side Effects

Adverse reactions associated with the use of the medication include a range of gastrointestinal, central nervous system, cardiovascular, renal, hematologic, ophthalmic, hypersensitivity, and other reactions.

Gastrointestinal adverse reactions may include intrahepatic cholestatic jaundice, pancreatitis, nausea, appetite disturbance, taste alteration, vomiting, diarrhea, constipation, anorexia, gastric irritation, and cramping.

Central nervous system effects reported by patients include drowsiness and fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, and paresthesias.

Cardiovascular reactions can manifest as tachycardia, shortness of breath, chest pain, and orthostatic hypotension, which may be exacerbated by the consumption of alcohol, barbiturates, or narcotics.

Renal adverse reactions include acute renal failure, acute interstitial nephritis, renal stones composed of triamterene in association with other calculus materials, and urine discoloration.

Hematologic reactions may involve leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, and megaloblastosis.

Ophthalmic reactions reported include xanthopsia and transient blurred vision.

Hypersensitivity reactions can be serious and include anaphylaxis, photosensitivity, rash, urticaria, purpura, necrotizing angiitis (vasculitis, cutaneous vasculitis), fever, and respiratory distress, including pneumonitis.

Other adverse reactions noted include muscle cramps and weakness, decreased sexual performance, and sialadenitis.

Hyperkalemia, characterized by an abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter), can occur with all potassium-conserving diuretic combinations, including triamterene and hydrochlorothiazide. This condition is more likely in patients with renal impairment, diabetes (even without evidence of renal impairment), or in elderly or severely ill patients. Due to the potential fatality of uncorrected hyperkalemia, serum potassium levels must be monitored frequently, especially in patients initiating treatment with triamterene and hydrochlorothiazide, when dosages are adjusted, or during any illness that may affect renal function.

Additionally, hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms typically include an acute onset of decreased visual acuity or ocular pain and may occur within hours to weeks of initiating treatment. Untreated acute angle-closure glaucoma can result in permanent vision loss, and the primary treatment is the rapid discontinuation of hydrochlorothiazide.

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 reduce arterial responsiveness to norepinephrine; however, this effect does not compromise the therapeutic efficacy of norepinephrine as a pressor agent. Conversely, thiazides may increase responsiveness to neuromuscular blocking agents such as tubocurarine, necessitating careful monitoring of neuromuscular function during concurrent use.

The 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.

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

Potassium-sparing diuretics should be used with extreme caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to a markedly increased risk of hyperkalemia. Frequent monitoring of serum potassium levels is essential to prevent potential complications.

Lastly, it is important to note that triamterene and quinidine share similar fluorescence spectra, which may interfere with the accurate measurement of quinidine levels when both agents are used concurrently. Clinicians should consider this interaction when interpreting quinidine levels in patients receiving triamterene and hydrochlorothiazide.

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, 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, 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 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.

For patients with mild renal functional impairment, the use of this medication should be approached with caution. Such patients should not receive this drug without ongoing and careful monitoring of serum electrolytes to mitigate potential risks associated with treatment.

Pregnancy

The safety of triamterene and hydrochlorothiazide tablets during pregnancy has not been established, as there are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted specifically for triamterene and hydrochlorothiazide tablets; however, a One Generation Study in rats using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day) showed no evidence of teratogenicity at doses significantly higher than the Maximum Recommended Human Dose (MRHD). Specifically, these doses were 15 and 30 times the MRHD based on body weight, and 3.1 and 6.2 times the MRHD based on body-surface area.

Reproduction studies with triamterene in rats at doses up to 20 times the MRHD (body weight) and 6 times the MRHD (body-surface area) also did not demonstrate fetal harm. Similarly, hydrochlorothiazide administered to pregnant mice and rats during critical periods of organogenesis at doses up to 3,000 mg/kg/day for mice and 1,000 mg/kg/day for rats did not show evidence of fetal harm, although these doses were multiples of the MRHD.

It is important to note that animal studies are not always predictive of human outcomes. Therefore, triamterene and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefits justify the risks to the fetus. The use of these medications requires careful consideration of the anticipated benefits against possible hazards, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults. Additionally, both triamterene and hydrochlorothiazide have been shown to cross the placental barrier and appear in cord blood, further necessitating a cautious approach in pregnant patients.

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, defined as an abnormal elevation of serum potassium levels (≥5.5 mEq/liter), particularly when using potassium-conserving diuretic combinations such as triamterene and hydrochlorothiazide. This risk is further heightened in patients with diabetes, elderly individuals, or those who are severely ill. Due to the potential for fatal outcomes associated with uncorrected hyperkalemia, serum potassium levels must be monitored at frequent intervals, especially when initiating therapy with triamterene and hydrochlorothiazide, adjusting dosages, or during any illness that may affect renal function.

In cases where hyperkalemia is detected, it is imperative to discontinue triamterene and hydrochlorothiazide immediately and consider substituting with a thiazide diuretic alone. If serum potassium levels exceed 6.5 mEq/liter, more aggressive interventions are warranted, which may include intravenous administration of calcium chloride or sodium bicarbonate, and/or the administration of glucose with a rapid-acting insulin preparation. Cationic exchange resins, such as sodium polystyrene sulfonate, may also be utilized. Persistent hyperkalemia may necessitate dialysis.

The development of hyperkalemia is accentuated in patients with renal impairment, and those with mild renal functional impairment should not receive this combination without close and continuous monitoring of serum electrolytes. Cumulative drug effects may occur in patients 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.

Additionally, hyperkalemia has been reported in diabetic patients using potassium-conserving agents, even in the absence of apparent renal impairment. Therefore, triamterene and hydrochlorothiazide should be avoided in diabetic patients, or if used, serum electrolytes must be monitored frequently.

Caution is advised when using triamterene and hydrochlorothiazide in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to their potassium-sparing properties. Furthermore, 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. If this combination is employed, frequent evaluations of acid/base balance and serum electrolytes are essential.

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 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 investigating 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 has been shown to have no adverse effects on the fertility of both male and female mice and rats when these species were exposed to dietary 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 by 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. These doses represent 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 by the National Toxicology Program, treated these animals with hydrochlorothiazide at doses up to 600 mg/kg/day for mice and 100 mg/kg/day for rats. On a body-weight basis, these doses are 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. 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.

Triamterene was not found to be 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 those using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test), the CHO test for chromosomal aberrations, or 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 obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in mouse lymphoma cell (mutagenicity) assays at concentrations of hydrochlorothiazide ranging from 43 to 1300 mcg/mL. Additionally, positive results were observed 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 from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who have received large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk 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 significantly higher risk, with an estimated 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing, using sunscreen with a high SPF, and 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 frequently, particularly in patients initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of conditions that may affect renal function. Clinicians are advised to perform serum electrolyte determinations at appropriate intervals to identify potential imbalances. Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, especially for elderly patients and those with suspected or confirmed hepatic disease or renal insufficiencies.

Patients prescribed hydrochlorothiazide should be counseled to protect their skin from sun exposure and to participate in regular skin cancer screenings. It is important to note that hydrochlorothiazide has been linked to an increased risk of nonmelanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients receiving high cumulative doses. The overall risk for SCC in the general population is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of 50,000 mg or more, the risk increases to about one additional case per 6,700 patients per year.

FDA Insert (PDF)

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

View full prescribing information (PDF)