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, classified as 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, USP 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 who require a thiazide diuretic but cannot risk the development of hypokalemia.

This medication may be utilized 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 inappropriate, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support 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 individuals. However, dependent edema resulting from venous return restriction due to an expanded uterus should be managed through elevation of the lower extremities and the use of support hose, rather than diuretics, which are illogical and unnecessary in this context.

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 generalized edema in many pregnant women. 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 one to two capsules administered once daily. Healthcare professionals should ensure appropriate monitoring of serum potassium levels and assess the clinical effect during treatment.

Contraindications

Triamterene and hydrochlorothiazide capsules are contraindicated in the following situations:

Use is contraindicated in patients receiving other potassium-sparing agents, such as spironolactone or amiloride, as well as other formulations containing triamterene. The use of potassium-containing salt substitutes is also prohibited due to the risk of hyperkalemia.

Potassium supplementation is contraindicated except in severe cases of hypokalemia, as it may lead to rapid increases in serum potassium levels.

These capsules are not to be administered to patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the potential for exacerbating renal function.

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

Additionally, the use of triamterene and hydrochlorothiazide capsules is contraindicated in patients with preexisting elevated serum potassium levels.

Warnings and Precautions

Hyperkalemia is a significant concern associated with the use of triamterene and hydrochlorothiazide capsules, as it can lead to an abnormal elevation of serum potassium levels (≥ 5.5 mEq/liter). 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 in the presence of any illness that may affect renal function.

Laboratory Tests

Serum Potassium: The normal range for serum potassium in adults is 3.5 to 5 mEq per liter, with 4.5 mEq often serving as a reference point. Should hypokalemia occur, appropriate corrective measures, such as potassium supplementation or increased dietary intake of potassium-rich foods, should be implemented cautiously, accompanied by frequent monitoring of serum potassium levels. Persistent potassium levels exceeding 6 mEq per liter necessitate careful observation and treatment. If laboratory results indicate an abnormal elevation of serum potassium, corrective measures for hypokalemia must be discontinued immediately. In such cases, triamterene and hydrochlorothiazide capsules should be discontinued, and a thiazide diuretic alone should be considered until potassium levels normalize.

Serum Creatinine and BUN: The administration of triamterene and hydrochlorothiazide may lead to elevated blood urea nitrogen (BUN) and creatinine levels, which are typically attributed to a reversible reduction in glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia), rather than renal toxicity. These levels generally return to normal upon discontinuation of the medication. If azotemia worsens, triamterene and hydrochlorothiazide capsules should be discontinued. Regular monitoring of BUN and serum creatinine is advised, particularly in elderly patients and those with suspected or confirmed renal insufficiency.

Serum PBI: It is noted that thiazides may reduce serum protein-bound iodine (PBI) levels without causing any signs of thyroid disturbance.

Parathyroid Function: Prior to conducting tests for parathyroid function, thiazides should be discontinued, as they decrease calcium excretion. Pathological changes in the parathyroid glands, characterized by hypercalcemia and hypophosphatemia, have been observed in a limited number of patients undergoing prolonged thiazide therapy.

Healthcare professionals are advised to remain vigilant regarding these warnings and to implement appropriate monitoring protocols to ensure patient safety during treatment with triamterene and hydrochlorothiazide capsules.

Side Effects

Adverse reactions associated with the use of the medication include a range of serious and common effects, which are categorized below.

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

Common adverse reactions observed in clinical trials and postmarketing experiences include metabolic disturbances such as diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia. Gastrointestinal symptoms may present as jaundice and/or liver enzyme abnormalities, pancreatitis, nausea and vomiting, diarrhea, constipation, and abdominal pain. Central nervous system effects can include weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo. Musculoskeletal complaints may involve muscle cramps, while ophthalmic effects can include xanthopsia and transient blurred vision. Skin reactions may range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis, including toxic epidermal necrolysis.

In neonates and infants, rare occurrences of thrombocytopenia and pancreatitis have been noted in newborns whose mothers received thiazides during pregnancy.

It is important to monitor serum potassium levels, as hyperkalemia (defined as an abnormal elevation of serum potassium levels greater than or equal to 5.5 mEq/liter) can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide capsules. This condition is particularly likely in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or those who are severely ill. Uncorrected hyperkalemia may be fatal, necessitating frequent monitoring of serum potassium levels, especially when initiating treatment, changing dosages, or during 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 some cases.

Lithium should generally be avoided in conjunction with diuretics, including triamterene and hydrochlorothiazide capsules, as diuretics can reduce renal clearance of lithium, increasing the risk of toxicity. It is essential to consult the circulars for lithium preparations prior to initiating such therapy.

Thiazide diuretics may diminish arterial responsiveness to norepinephrine, although this effect does not compromise the therapeutic efficacy of norepinephrine. Additionally, thiazides can 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 agents, 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 anticoagulation.

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

Certain agents may promote serum potassium accumulation when used with triamterene, potentially leading to hyperkalemia, particularly in patients with renal insufficiency. These agents include blood products (which may contain significant potassium), 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 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 can affect the drug's therapeutic action.

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, may experience an increased risk of hyperkalemia, especially in the presence of renal impairment or diabetes, even in the absence of overt renal dysfunction. It is essential for healthcare providers to exercise caution when prescribing this medication to geriatric patients, as they may be more susceptible to adverse effects.

Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are significantly reduced in elderly patients, leading to increased plasma levels of these compounds. Consequently, dose adjustments may be necessary to mitigate the risk of toxicity in this population.

To ensure patient safety, periodic monitoring of blood urea nitrogen (BUN) and serum creatinine levels is recommended, particularly for elderly patients and those with suspected or confirmed renal insufficiency. This monitoring is crucial for identifying potential renal complications and adjusting treatment as needed.

Pregnancy

The use of triamterene and hydrochlorothiazide during pregnancy is classified as Pregnancy Category C. Animal reproduction studies have not been conducted to assess the potential for fetal harm; however, a One Generation Study in rats indicated no evidence of teratogenicity at doses significantly higher than the maximum recommended human dose (MRHD). Reproduction studies 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) also showed no evidence of harm to the fetus. Similarly, hydrochlorothiazide administered to pregnant mice and rats during major organogenesis at doses up to 3,000 mg/kg/day (mice) and 1,000 mg/kg/day (rats) did not demonstrate fetal harm.

Despite these findings, the safe use of triamterene and hydrochlorothiazide capsules in pregnant patients has not been established due to the absence of adequate and well-controlled studies in pregnant women. Therefore, these medications should only be used during pregnancy if the potential benefit justifies the risk to the fetus. It is important to note that thiazides and triamterene cross the placental barrier and can be detected in cord blood. The anticipated benefits must be carefully weighed against potential hazards to the fetus, which may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions. Consequently, the use of these medications during pregnancy should be approached with caution and only if clearly needed.

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 of hyperkalemia, particularly those with diabetes, even in the absence of overt renal dysfunction, as well as elderly or severely ill patients.

Serum potassium levels should be monitored at frequent intervals in these patients, especially when initiating treatment with triamterene and hydrochlorothiazide capsules, during any dosage adjustments, or in the presence of any illness that may affect renal function.

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, 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 scenario.

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, which approximated the composition of triamterene and hydrochlorothiazide capsules using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day), demonstrated no evidence of teratogenicity at these doses. These doses 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, respectively. 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 performed 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, without evidence of fetal harm. Hydrochlorothiazide was administered orally 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. These doses represent multiples of the MRHD of 3,000 for mice and 1,000 for rats based on body weight, and 282 for mice and 206 for rats based on body-surface area, with no evidence of fetal harm observed.

Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of thiazides and triamterene 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 that have been reported in adults.

Long-term studies evaluating the triamterene/hydrochlorothiazide combination or triamterene alone have not been conducted. Hydrochlorothiazide was subjected to two-year feeding studies in mice and rats under the National Toxicology Program (NTP), with doses of up to 600 mg/kg/day for mice and 100 mg/kg/day for rats. These doses are 600 times and 100 times the MRHD for hydrochlorothiazide at 50 mg/day based on body weight, and 56 times and 21 times the MRHD based on body-surface area, respectively. These studies revealed no evidence of carcinogenic potential in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test with Salmonella typhimurium strains and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, as well as 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 mouse Lymphoma Cell mutagenicity assays at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Studies examining 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 species 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 a range of adverse reactions reported voluntarily or through surveillance programs. These include anaphylaxis, rash, urticaria, and subacute cutaneous lupus erythematosus-like reactions. Photosensitivity, arrhythmia, and postural hypotension have also been noted. Metabolic disturbances such as diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia were reported.

Hepatic events, including jaundice and/or liver enzyme abnormalities, as well as pancreatitis, have been documented. Gastrointestinal symptoms such as nausea and vomiting, diarrhea, constipation, and abdominal pain were also reported. Renal complications include acute renal failure (with one case of irreversible renal failure), interstitial nephritis, renal stones primarily composed of triamterene, elevated BUN and serum creatinine, and abnormal urinary sediment.

Hematological events such as leukopenia, thrombocytopenia, purpura, megaloblastic anemia, aplastic anemia, and agranulocytosis have been observed. Other reported symptoms include muscle cramps, weakness, fatigue, dizziness, headache, dry mouth, impotence, sialadenitis, paresthesias, vertigo, and xanthopsia. Visual disturbances such as transient blurred vision were also noted.

Respiratory events, including allergic pneumonitis, pulmonary edema, and respiratory distress, have been reported. Vascular complications such as necrotizing vasculitis and exacerbation of lupus were documented. Serious skin reactions, including erythema multiforme (including Stevens-Johnson syndrome) and exfoliative dermatitis (including toxic epidermal necrolysis), have been observed. Additionally, thrombocytopenia and pancreatitis were reported in neonates and infants whose mothers received thiazides during pregnancy.

Patient Counseling

Patients should be advised to monitor their serum potassium levels regularly, particularly when initiating treatment or adjusting dosages. In the event that hyperkalemia is suspected, patients should be made aware of warning signs such as paresthesias, muscular weakness, fatigue, flaccid paralysis, bradycardia, and shock, and they should seek medical attention promptly.

Patients must be instructed to discontinue triamterene and hydrochlorothiazide capsules immediately if hyperkalemia is confirmed. They should be advised to substitute with a thiazide diuretic alone until potassium levels normalize. Caution should be exercised when administering triamterene and hydrochlorothiazide capsules to patients with diabetes, as thiazides may induce hyperglycemia and alter insulin requirements.

It is important to inform patients that the use of diuretics in otherwise healthy pregnant women is inappropriate and poses unnecessary risks to both the mother and fetus. If the use of triamterene and hydrochlorothiazide capsules is considered essential during pregnancy, the potential benefits must be carefully weighed against possible risks to the fetus.

Nursing mothers should be advised that triamterene is excreted in animal milk and may also appear in human milk; therefore, if the combination drug is deemed necessary, nursing should be discontinued. Patients should also be informed that thiazides and triamterene can cross the placental barrier and be present in cord blood, necessitating careful consideration of the potential hazards to the fetus.

Finally, patients should be encouraged to report any side effects to their healthcare provider and may also report side effects to the FDA at 1-800-FDA-1088.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the 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 mEq per liter, with 4.5 mEq often serving 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 per liter, 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 and increased intracellular potassium. Corrective measures for hypokalemia should be halted if serum potassium levels become abnormally elevated, and triamterene and hydrochlorothiazide capsules should be discontinued, with a thiazide diuretic substituted 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 indicating 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 parathyroid glands with hypercalcemia and hypophosphatemia, common complications associated with hyperparathyroidism, such as bone resorption and peptic ulceration, have not been observed.

FDA Insert (PDF)

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

View full prescribing information (PDF)