Triamterene/Hydrochlorothiazide

Description

Each capsule of triamterene and hydrochlorothiazide for oral use features an opaque yellow cap and an opaque white body, containing 37.5 mg of triamterene and 25 mg of hydrochlorothiazide, imprinted with the code 855. Hydrochlorothiazide, a diuretic and antihypertensive agent, is chemically defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It exhibits very slight solubility in water, with greater solubility in sodium hydroxide solution, n-butylamine, and dimethyl formamide, while being sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids.

Triamterene, an antikaliuretic agent, is identified as 2,4,7-triamino-6-phenylpteridine. It is soluble in formic acid and sparingly soluble in methoxyethanol, with very slight solubility in acetic acid, alcohol, and dilute mineral acids. Triamterene is practically insoluble in water, benzene, ether, chloroform, and dilute alkali hydroxides.

In addition to the active ingredients, each capsule contains the following inactive components: citric acid monohydrate, colloidal silicon dioxide, croscarmellose sodium, gelatin, glycine, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and titanium dioxide. The capsules are printed with black pharmaceutical ink, which includes ferric oxide black, potassium hydroxide, and shellac. These capsules meet Drug Release Test 3 as specified in the current USP monograph for Triamterene and Hydrochlorothiazide Capsules.

Uses and Indications

Triamterene and hydrochlorothiazide capsules are indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide monotherapy. These capsules are also indicated for patients requiring a thiazide diuretic where the risk of hypokalemia must be avoided.

This medication may be administered alone or as an adjunct to other antihypertensive agents, such as beta-blockers. It is important to note that triamterene and hydrochlorothiazide capsules may enhance the effects of these agents, 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.

Diuretics may be indicated during pregnancy when edema is due to pathological causes, 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.

Normal pregnancy is associated with hypervolemia, which is not harmful to the mother or fetus in the absence of cardiovascular disease, although it may lead to edema. If this edema causes discomfort, increased recumbency is often sufficient for relief. In rare cases where extreme discomfort persists despite rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dose of triamterene and hydrochlorothiazide capsules is 1 or 2 capsules administered once daily. Healthcare professionals are advised to monitor serum potassium levels and assess the clinical effect regularly to ensure patient safety and therapeutic efficacy.

Contraindications

Triamterene and hydrochlorothiazide capsules are contraindicated in the following situations:

• Patients receiving other potassium-sparing agents, including spironolactone, amiloride, or other formulations containing triamterene, due to the risk of hyperkalemia.

• Use of potassium-containing salt substitutes is prohibited, as it may lead to elevated serum potassium levels.

• Potassium supplementation is contraindicated except in severe cases of hypokalemia, to avoid the risk of hyperkalemia.

• Patients with anuria, acute or chronic renal insufficiency, or significant renal impairment should not use these capsules, as renal function is critical for drug elimination.

• Hypersensitivity to either triamterene or hydrochlorothiazide, or to other sulfonamide-derived drugs, is a contraindication.

• The use of these capsules is also contraindicated in patients with pre-existing elevated serum potassium levels, due to the potential for further increases in potassium.

Warnings and Precautions

Hyperkalemia is a significant risk associated with the use of triamterene and hydrochlorothiazide capsules, as it can lead to an abnormal elevation of serum potassium levels (≥ 5.5 mEq/L). This condition is particularly prevalent in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, and those who are severely ill. Due to the potential fatality of uncorrected hyperkalemia, it is imperative that serum potassium levels be monitored frequently, especially in patients initiating treatment with triamterene and hydrochlorothiazide capsules, during dosage adjustments, or when any illness may affect renal function.

In the event of hyperkalemia, it is recommended to discontinue triamterene and hydrochlorothiazide capsules and consider substituting with a thiazide diuretic alone until potassium levels normalize. Additionally, if there is an increase in azotemia, the capsules should also be discontinued. Regular monitoring of blood urea nitrogen (BUN) and serum creatinine levels is advised, particularly in elderly patients and those with suspected or confirmed renal insufficiency.

Laboratory Tests

Monitoring of serum potassium is essential, with the normal adult range being 3.5 to 5.0 mEq/L, and 4.5 mEq/L often used as a reference point. Should hypokalemia occur, corrective measures such as potassium supplementation or increased dietary intake of potassium-rich foods should be implemented cautiously, with frequent serum potassium determinations. Persistent potassium levels above 6 mEq/L necessitate careful observation and treatment, and any corrective measures for hypokalemia should be halted immediately if serum potassium levels rise abnormally.

Triamterene and hydrochlorothiazide may also elevate BUN and creatinine levels, which is typically due to a reversible reduction in glomerular filtration rate or intravascular fluid volume depletion (prerenal azotemia), rather than renal toxicity. These levels generally return to normal upon discontinuation of the capsules. Furthermore, thiazides may decrease serum protein-bound iodine (PBI) levels without indicating thyroid dysfunction. It is important to discontinue thiazides prior to conducting tests for parathyroid function, as they can affect calcium excretion.

Healthcare professionals are advised to remain vigilant regarding these warnings and precautions to ensure the safe use of triamterene and hydrochlorothiazide capsules in their patients.

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, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, and photosensitivity. Cardiovascular events such as arrhythmia and postural hypotension have also been reported. Renal complications may arise, including acute renal failure, with one case of irreversible renal failure documented, interstitial nephritis, and renal stones primarily composed of triamterene. Hematologic issues such as leukopenia, thrombocytopenia, purpura, megaloblastic anemia, aplastic anemia, agranulocytosis, and hemolytic anemia have been observed as well. Additionally, respiratory complications like allergic pneumonitis, pulmonary edema, and respiratory distress can occur.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal symptoms such as jaundice and/or liver enzyme abnormalities, pancreatitis, nausea, vomiting, diarrhea, constipation, and abdominal pain. Metabolic disturbances may manifest as diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia. Central nervous system effects such as weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo have also been noted. Musculoskeletal complaints, particularly muscle cramps, are common, as are ophthalmic issues like xanthopsia and transient blurred vision.

Skin reactions can be severe, including erythema multiforme, Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis. There is also a noted risk of necrotizing vasculitis and exacerbation of lupus. In neonates and infants, rare cases of thrombocytopenia and pancreatitis have been reported in newborns whose mothers received thiazides during pregnancy.

Postmarketing data indicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The overall risk for SCC is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

It is important to monitor serum potassium levels, as hyperkalemia (elevated serum potassium levels of ≥5.5 mEq/liter) can occur with potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide. This condition is more likely in patients with renal impairment, diabetes, the elderly, or those who are severely ill. Uncorrected hyperkalemia may be fatal, necessitating frequent monitoring, especially when initiating treatment, changing dosages, or in the presence of any illness that may affect renal function.

Drug Interactions

Potassium-sparing agents should be used with caution when administered alongside angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia. Monitoring of serum potassium levels is recommended in such cases.

The concurrent use of triamterene and hydrochlorothiazide capsules with chlorpropamide may elevate the risk of severe hyponatremia. Close monitoring of sodium levels is advised.

Caution is warranted when administering nonsteroidal anti-inflammatory agents, such as indomethacin, in patients taking triamterene and hydrochlorothiazide capsules, as there have been reports of acute renal failure in a few cases.

Lithium should generally not be co-prescribed with diuretics, including triamterene and hydrochlorothiazide capsules, as diuretics can reduce lithium's renal clearance, increasing the risk of toxicity. It is essential to consult the prescribing information for lithium preparations prior to initiating concomitant therapy.

Thiazide diuretics have been shown to decrease arterial responsiveness to norepinephrine, although this effect does not compromise the therapeutic efficacy of norepinephrine. Additionally, thiazides may enhance the neuromuscular blocking effects of nondepolarizing muscle relaxants, such as tubocurarine, necessitating caution in surgical patients.

The combination of hydrochlorothiazide with amphotericin B, corticosteroids, or corticotropin (ACTH) may exacerbate electrolyte imbalances, particularly hypokalemia. However, the presence of triamterene may mitigate the hypokalemic effect.

Thiazides may potentiate the effects of other antihypertensive medications, necessitating careful monitoring of blood pressure and potential dosage adjustments.

The efficacy of oral anticoagulants may be diminished when used concurrently with hydrochlorothiazide, and dosage adjustments may be required to maintain therapeutic effectiveness.

Triamterene and hydrochlorothiazide may elevate blood uric acid levels, which may necessitate dosage adjustments of antigout medications to manage hyperuricemia and gout effectively.

Certain agents, when used in conjunction with triamterene, may lead to serum potassium accumulation and potentially result in hyperkalemia, particularly in patients with renal insufficiency. These agents include blood products (which may contain significant potassium levels), low-salt milk, potassium-containing medications (such as parenteral penicillin G potassium), and salt substitutes.

Exchange resins, such as sodium polystyrene sulfonate, can lower serum potassium levels through sodium replacement; however, fluid retention may occur due to increased sodium intake.

Chronic or excessive use of laxatives may lead to reduced serum potassium levels by promoting excessive potassium loss from the gastrointestinal tract, potentially interfering with the potassium-retaining effects of triamterene.

The effectiveness of methenamine may be reduced when used concurrently with hydrochlorothiazide due to the alkalinization of urine, which may necessitate monitoring and potential adjustments in therapy.

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. Caution is advised when prescribing this medication to geriatric patients, as the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are often reduced in this population, leading to increased plasma levels of the drug.

For elderly patients with mild renal functional impairment, it is essential to avoid the use of this medication without implementing frequent and ongoing monitoring of serum electrolytes. Additionally, periodic assessments of blood urea nitrogen (BUN) or serum creatinine levels should be conducted, particularly in elderly patients and those with suspected or confirmed renal insufficiency, to ensure patient safety and effective management of potential adverse effects.

Pregnancy

The safety of triamterene and hydrochlorothiazide capsules during pregnancy has not been established, as there are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not demonstrated teratogenic effects; however, these studies are not always predictive of human outcomes. In a One Generation Study conducted in rats, doses approximating the composition of triamterene and hydrochlorothiazide capsules (30:30 mg/kg/day) showed no evidence of teratogenicity at levels significantly above 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 involving hydrochlorothiazide in pregnant mice and rats during critical periods of organogenesis also indicated no fetal harm at high doses, which were multiples of the MRHD. However, thiazides and triamterene are known to cross the placental barrier and can be detected in cord blood. Therefore, the use of these medications in pregnant patients should be approached with caution, weighing the potential benefits against the risks to the fetus. Possible hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

In summary, triamterene and hydrochlorothiazide should only be used during pregnancy if the potential benefit justifies the risk to the fetus, and healthcare providers should carefully consider the individual circumstances of each patient.

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 similar excretion may occur in humans. 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 of hyperkalemia when using potassium-sparing diuretic combinations, such as triamterene and hydrochlorothiazide capsules. This risk is further heightened in patients with diabetes, even in the absence of renal impairment, as well as in elderly or severely ill patients.

It is essential to monitor serum potassium levels at frequent intervals in patients with reduced kidney function, particularly when initiating treatment with triamterene and hydrochlorothiazide capsules, during dosage adjustments, or in the presence of any illness that may affect renal function.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise clinical judgment when considering the use of this medication in patients with liver problems, as the absence of data does not preclude the need for careful evaluation of each patient's unique circumstances.

Overdosage

In cases of overdosage, the primary concern is the potential for electrolyte imbalance. Symptoms that may manifest include polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes.

Management of hypotension, if it occurs, may involve the administration of pressor agents such as levarterenol to help maintain blood pressure. It is crucial to carefully evaluate the patient's electrolyte pattern and fluid balance to guide further treatment.

Immediate intervention is recommended, which includes the induction of gastric evacuation through emesis or gastric lavage. It is important to note that there is no specific antidote available for this overdosage.

Reports have indicated that ingestion of 50 tablets of a product containing 50 mg of triamterene and 25 mg of hydrochlorothiazide can lead to reversible acute renal failure. While triamterene is predominantly protein-bound (approximately 67%), there may still be some benefit to dialysis in cases of significant overdosage.

Nonclinical Toxicology

Animal reproduction studies to assess the potential for fetal harm associated with triamterene and hydrochlorothiazide have not been conducted. 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 these doses, which correspond to 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. The safe use of triamterene and hydrochlorothiazide capsules during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women.

Reproduction studies involving triamterene have been conducted in rats at doses up to 20 times the MRHD based on body weight and 6 times the human dose based on body surface area, with no evidence of fetal harm. Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses of up to 3,000 mg/kg/day for mice and 1,000 mg/kg/day for rats. These doses, which are multiples of the MRHD, also showed no evidence of fetal harm.

Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of these agents in pregnant women necessitates careful consideration of the anticipated benefits against potential risks to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

Long-term studies evaluating the triamterene/hydrochlorothiazide combination or triamterene alone have not been performed. Hydrochlorothiazide was subjected to two-year feeding studies in mice and rats, conducted by the National Toxicology Program (NTP), with doses reaching 600 mg/kg/day in mice and 100 mg/kg/day in rats. These doses represent 600 times and 100 times the MRHD for hydrochlorothiazide, respectively. The studies revealed no evidence of carcinogenic potential in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

Studies assessing the mutagenic potential of the triamterene/hydrochlorothiazide combination or triamterene alone have not been conducted. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test and tests for chromosomal aberrations. However, positive results were observed in the in vitro CHO Sister Chromatid Exchange test and in mouse lymphoma cell assays at specific concentrations. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay.

Studies investigating the effects of the triamterene/hydrochlorothiazide combination or triamterene alone on animal reproductive function have not been conducted. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these animals were exposed to 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 100 times the MRHD for mice and 4 times the MRHD for rats based on body weight, and 9.4 times and 0.8 times the MRHD based on body surface area, respectively.

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 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 as defined by the United States Pharmacopeia (USP). 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 and efficacy.

Additional Clinical Information

Serum potassium levels in adults typically range from 3.5 to 5.0 mEq/L, with 4.5 mEq often used as a reference point. In cases of hypokalemia, clinicians should implement corrective measures such as potassium supplementation or dietary adjustments, monitoring serum potassium levels closely. If potassium levels exceed 6 mEq/L, careful observation and treatment are necessary. It is important to note that serum potassium levels may not accurately reflect total body potassium concentration, and a rise in plasma pH can lead to decreased plasma potassium levels. Corrective measures for hypokalemia should be halted if serum potassium levels become abnormally elevated, and triamterene and hydrochlorothiazide capsules should be discontinued, substituting with a thiazide diuretic until potassium levels normalize.

Triamterene and hydrochlorothiazide may elevate blood urea nitrogen (BUN) and creatinine levels, likely due to a reversible reduction in glomerular filtration rate or intravascular fluid volume depletion, rather than renal toxicity. These levels typically return to normal upon discontinuation of the medication. Regular monitoring of BUN and serum creatinine is advised, particularly in elderly patients and those with renal insufficiency. Additionally, thiazides can lower serum protein-bound iodine (PBI) levels without causing thyroid dysfunction. Prior to testing for parathyroid function, thiazides should be discontinued, as they decrease calcium excretion. While some patients on prolonged thiazide therapy have shown pathological changes in the parathyroid glands, common complications associated with hyperparathyroidism have not been observed.

FDA Insert (PDF)

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

View full prescribing information (PDF)