Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide combines triamterene, a potassium-conserving diuretic, with the natriuretic agent, hydrochlorothiazide. Each Triamterene and Hydrochlorothiazide 37.5 mg/25 mg Tablet, USP contains 37.5 mg of Triamterene, USP and 25 mg of Hydrochlorothiazide, USP. Each Triamterene and Hydrochlorothiazide 75 mg/50 mg Tablet, USP contains 75 mg of Triamterene, USP and 50 mg of Hydrochlorothiazide, USP. Triamterene is chemically identified as 2,4,7-triamino-6-phenylpteridine and is practically insoluble in water, benzene, chloroform, ether, and dilute alkali hydroxides. It is soluble in formic acid and sparingly soluble in methoxyethanol, while being very slightly soluble in acetic acid, alcohol, and dilute mineral acids. Hydrochlorothiazide 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. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. The tablets for oral administration contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 37.5 mg/25 mg tablets also contain D&C Yellow No.10 Aluminum Lake and FD&C Blue No.1 Aluminum Lake.

Uses and Indications

This fixed combination drug is indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide alone. It is 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: 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, similar to their use in non-pregnant patients. 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 generally not harmful and is often accompanied by edema. If this edema causes significant 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 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 who require hydrochlorothiazide therapy but 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 either two 37.5 mg/25 mg tablets daily as a single dose or 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. 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 individuals who are hypersensitive to triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs, as this may lead to 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. Given 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 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 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 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; 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 disturbances in fluid and electrolyte balance could precipitate hepatic coma. Additionally, triamterene has been associated with the formation of renal stones, and its use should be approached with caution in individuals with a history of renal lithiasis. As a weak folic acid antagonist, triamterene may contribute to megaloblastosis in patients with diminished folic acid stores, necessitating periodic blood evaluations. Furthermore, hyperuricemia and acute gout may be precipitated in certain patients undergoing thiazide therapy.

In summary, regular monitoring of serum potassium levels, serum electrolytes, and periodic BUN and creatinine assessments are critical for the safe administration of triamterene and hydrochlorothiazide, particularly in at-risk populations.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment with triamterene and hydrochlorothiazide. These reactions can be categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, photosensitivity, and respiratory distress, including pneumonitis. Hematologic reactions may manifest as leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, and megaloblastosis. Renal complications can include acute renal failure and acute interstitial nephritis. Additionally, patients may experience acute myopia and secondary angle-closure glaucoma, which can lead to permanent vision loss if untreated.

Common gastrointestinal adverse reactions reported include nausea, vomiting, diarrhea, constipation, and appetite disturbance. Other gastrointestinal effects may involve jaundice (intrahepatic cholestatic jaundice), gastric irritation, cramping, and taste alteration. Central nervous system effects are also prevalent, with patients reporting drowsiness, fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, and paresthesias.

Cardiovascular reactions may include tachycardia, shortness of breath, chest pain, and orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, or narcotics. Patients may also experience renal issues such as urine discoloration and renal stones composed of triamterene in association with other calculus materials.

Other notable adverse reactions include muscle cramps and weakness, decreased sexual performance, and sialadenitis. Patients should be monitored for hyperkalemia, particularly those with renal impairment, diabetes, or those who are elderly or severely ill, as uncorrected hyperkalemia can be fatal. Electrolyte imbalances and increases in blood urea nitrogen (BUN) levels may also occur, necessitating careful monitoring for signs of fluid and electrolyte disturbances.

In clinical trials and postmarketing experiences, it has been noted that triamterene is a weak folic acid antagonist, which may contribute to megaloblastosis in patients with decreased folic acid stores. Therefore, periodic blood evaluations are recommended in these cases. Caution is advised when administering this medication to patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazide therapy.

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 conjunction with other antihypertensives.

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 requiring norepinephrine for blood pressure support.

The concomitant use of lithium with diuretics is contraindicated, as diuretics can reduce renal clearance of lithium, thereby increasing the risk of lithium toxicity. Regular monitoring of lithium levels is recommended for patients who may require diuretic therapy.

Caution is warranted when administering indomethacin alongside triamterene and hydrochlorothiazide, as acute renal failure has been reported in such cases. Clinicians should evaluate renal function closely in patients receiving this combination.

When potassium-sparing agents are used in conjunction with ACE inhibitors, there is an increased risk of hyperkalemia. It is advisable to monitor serum potassium levels frequently to mitigate this risk.

Lastly, triamterene and hydrochlorothiazide may interfere with the measurement of quinidine due to overlapping fluorescence spectra. This potential interaction should be taken into account when interpreting quinidine levels in patients receiving this combination.

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, and healthcare professionals are advised to consider the lack of data when prescribing to this population.

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.

Additionally, 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, careful consideration of dosage adjustments may be necessary to mitigate the risk of adverse effects.

Periodic assessments of blood urea nitrogen (BUN) and creatinine levels are also recommended, as elevations in these parameters may occur more frequently in geriatric patients. Regular monitoring and appropriate dose modifications are crucial to ensure the safety and efficacy of treatment in this vulnerable population.

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. Animal reproduction studies have not been conducted specifically to determine the potential for fetal harm from triamterene and hydrochlorothiazide. However, a One Generation Study in rats, utilizing a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day), demonstrated no evidence of teratogenicity at doses that were 15 and 30 times the Maximum Recommended Human Dose (MRHD) based on body weight, and 3.1 and 6.2 times the MRHD based on body-surface area.

Reproduction studies involving triamterene in rats at doses up to 20 times the MRHD (body weight) and 6 times the MRHD (body-surface area) also showed no evidence of fetal harm. Hydrochlorothiazide has been administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 mg/kg/day for mice and 1000 mg/kg/day for rats, with no observed fetal harm at these levels, which are significantly higher than the MRHD.

It is important to note that thiazides and triamterene can cross the placental barrier and appear in cord blood. Therefore, the use of these medications in pregnant patients should be approached with caution, weighing the anticipated benefits against potential risks to the fetus. Possible hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been observed in adults. Consequently, triamterene and hydrochlorothiazide should only be used during pregnancy if clearly needed.

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. Thiazides are known to be excreted in human breast milk as well.

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. It is essential to monitor serum potassium levels 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.

The risk of developing hyperkalemia is heightened in patients taking potassium-sparing diuretics, particularly in those with reduced kidney function. For patients with mild renal functional impairment, the use of this medication should be approached with caution, necessitating frequent and ongoing 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 pharmacologically active metabolite of triamterene, leading to increased plasma levels in elderly patients and those with renal impairment. If triamterene and hydrochlorothiazide is prescribed to patients with renal impairment, it is critical to conduct frequent evaluations of acid/base balance and serum electrolytes 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 overdose situations 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 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. Induction of emesis or gastric lavage may be considered to reduce the absorption of the drugs.

Continuous monitoring of serum electrolyte levels and fluid balance is essential in cases of overdose. Supportive measures should be implemented as necessary to maintain hydration, restore electrolyte balance, and ensure proper organ function.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of triamterene and hydrochlorothiazide tablets, as well as the triamterene/hydrochlorothiazide combination, have not been conducted. However, non-teratogenic effects of hydrochlorothiazide have been observed in studies involving mice and rats. In these studies, no adverse effects on fertility were noted in either sex when 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 triamterene and hydrochlorothiazide tablets or the 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 with 0, 100, 200, or 400 ppm triamterene. 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, 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 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 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 hydrochlorothiazide (50 mg/day or 1 mg/kg/day based on a 50 kg patient) when assessed on a body-weight basis, and 56 times (in mice) and 21 times (in rats) on a body-surface area basis. These studies revealed 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 triamterene and hydrochlorothiazide tablets or the combination have not been performed. Triamterene was found to be non-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 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 using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, 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. 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, 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.

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 risks associated with sun exposure while on hydrochlorothiazide and encouraged to report any unusual skin changes or concerns 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° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° 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

Clinicians should conduct laboratory tests to monitor serum electrolytes at appropriate intervals to detect potential imbalances, particularly in patients who are 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances. Clinicians should inform patients that hypokalemia may heighten the heart's sensitivity to digitalis toxicity, and that triamterene, a weak folic acid antagonist, may lead to megaloblastosis in patients with diminished folic acid stores. Additionally, thiazide therapy may cause hyperuricemia or precipitate acute gout, alter insulin requirements in diabetic patients, and potentially exacerbate systemic lupus erythematosus, even in those without a prior history of allergy or asthma.

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)