Triamterene/Hydrochlorothiazide

Description

Each capsule for oral administration contains 37.5 mg of triamterene and 25 mg of hydrochlorothiazide. Hydrochlorothiazide, a diuretic and antihypertensive agent, is characterized by the molecular formula C₇H₈ClN₃O₄S₂ and a molecular weight of 297.74. It is slightly soluble in water, soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide, and sparingly soluble in methanol. Its structural formula is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

Triamterene, an antikaliuretic agent, has a molecular formula of C₁₂H₁₁N₇ and a molecular weight of 253.26. At 50°C, it is practically insoluble in water (less than 0.1%), but it is soluble in formic acid, sparingly soluble in methoxyethanol, and very soluble in alcohol. Its structural formula is 2,4,7-triamino-6-phenylpteridine.

The inactive ingredients include lactose monohydrate, pregelatinized starch, sodium starch glycolate, polysorbate 80, citric acid anhydrous, povidone, and magnesium stearate. The capsule shell is composed of titanium dioxide and gelatin, while the capsule imprinting ink contains shellac glaze in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, ethanol, methanol, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #1 Aluminum Lake, and D&C Yellow #10 Aluminum Lake.

Triamterene and hydrochlorothiazide capsules, USP, comply with USP Dissolution Test 3 as outlined in the current USP monograph for these 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 requiring a thiazide diuretic where the risk of hypokalemia must be avoided.

This medication may be utilized as a standalone treatment or in conjunction with 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. During normal pregnancy, hypervolemia occurs, which is not harmful to the mother or fetus in the absence of cardiovascular disease, although it may be associated with edema.

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 these cases is considered illogical and unnecessary. In instances where edema causes significant discomfort and is unrelieved by rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dose of triamterene and hydrochlorothiazide capsules, USP, 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, USP are contraindicated in the following situations:

Patients receiving other potassium-sparing agents, such as spironolactone or amiloride, or other formulations containing triamterene, should not use this medication due to the risk of hyperkalemia. Additionally, the use of potassium-containing salt substitutes is contraindicated.

Potassium supplementation is contraindicated except in severe cases of hypokalemia, as it may lead to rapid increases in serum potassium levels. If potassium supplementation is deemed necessary, careful monitoring of serum potassium levels is required.

The use of triamterene and hydrochlorothiazide capsules, USP is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the potential for exacerbating renal function.

Patients with a known hypersensitivity to either drug in the formulation or to other sulfonamide-derived drugs should not use this medication.

Lastly, the use of triamterene and hydrochlorothiazide capsules, USP is contraindicated in patients with preexisting elevated serum potassium levels, as this may further increase the risk of hyperkalemia.

Warnings and Precautions

Hyperkalemia is a significant risk associated with the use of triamterene and hydrochlorothiazide capsules, USP. Patients may experience an abnormal elevation of serum potassium levels (≥ 5.5 mEq/liter), particularly those with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or 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 therapy with triamterene and hydrochlorothiazide capsules, USP, during dosage adjustments, or in the presence of any condition that may affect renal function.

Laboratory Tests

Serum Potassium: The normal range for serum potassium in adults is 3.5 to 5.0 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 serum potassium level assessments. If potassium levels rise persistently above 6 mEq per liter, careful observation and treatment are required. In cases where laboratory results indicate an abnormal elevation of serum potassium, corrective measures for hypokalemia must be discontinued immediately. In such instances, triamterene and hydrochlorothiazide capsules, USP should be discontinued, and a thiazide diuretic alone should be considered until potassium levels normalize.

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

Serum PBI: Thiazide diuretics may reduce serum protein-bound iodine (PBI) levels without causing any signs of thyroid dysfunction.

Parathyroid Function: Prior to conducting tests for parathyroid function, thiazides should be discontinued, as they decrease calcium excretion. Some patients on prolonged thiazide therapy have exhibited pathological changes in the parathyroid glands, characterized by hypercalcemia and hypophosphatemia. However, common complications associated with hyperparathyroidism, such as bone resorption and peptic ulceration, have not been observed.

Healthcare professionals are advised to remain vigilant regarding these warnings and to implement appropriate monitoring protocols to ensure patient safety during the administration of triamterene and hydrochlorothiazide capsules, USP.

Side Effects

Patients may experience a range of adverse reactions while using the 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. Additionally, metabolic disturbances may occur, including hyperkalemia, which is highlighted in the boxed warning due to its potential severity. Hyperkalemia can lead to abnormal elevation of serum potassium levels (≥5.5 mEq/liter) and is more likely in patients with renal impairment, diabetes, the elderly, or those who are severely ill. Monitoring of serum potassium levels is essential, particularly when initiating treatment or adjusting dosages.

Other serious reactions include acute renal failure, with one case reported as irreversible, 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 also been observed. Respiratory complications, including allergic pneumonitis, pulmonary edema, and respiratory distress, are noteworthy.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal symptoms such as nausea, vomiting, diarrhea, constipation, abdominal pain, and jaundice or liver enzyme abnormalities. Patients may also experience musculoskeletal symptoms like muscle cramps, central nervous system effects including weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo. Ophthalmic effects such as xanthopsia and transient blurred vision have been noted.

Miscellaneous adverse reactions include impotence, sialadenitis, necrotizing vasculitis, and exacerbation of lupus. In neonates and infants, rare occurrences of thrombocytopenia and pancreatitis have been reported in newborns whose mothers received thiazides during pregnancy.

Skin reactions can be severe, including erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis.

Patients should be monitored closely for these adverse reactions, particularly those that are serious or potentially life-threatening.

Drug Interactions

Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.

Pharmacodynamic Interactions

Concurrent use of triamterene and hydrochlorothiazide capsules, USP with chlorpropamide may increase the risk of severe hyponatremia. Additionally, caution is advised when administering nonsteroidal anti-inflammatory agents, such as indomethacin, to patients taking triamterene and hydrochlorothiazide capsules, USP, as a possible interaction resulting in acute renal failure has been reported.

Thiazide diuretics, including hydrochlorothiazide, have been shown to decrease arterial responsiveness to norepinephrine, although this effect does not preclude the therapeutic use of norepinephrine. Furthermore, thiazides may enhance the paralyzing effect of nondepolarizing muscle relaxants, such as tubocurarine, necessitating caution in patients undergoing surgery.

Concurrent use of hydrochlorothiazide with amphotericin B, corticosteroids, or corticotropin (ACTH) may intensify electrolyte imbalances, particularly hypokalemia; however, the presence of triamterene may mitigate this effect. Thiazides may also potentiate the action of other antihypertensive drugs.

Pharmacokinetic Interactions

The effectiveness of oral anticoagulants may be diminished when used concurrently with hydrochlorothiazide, and dosage adjustments may be necessary. Triamterene and hydrochlorothiazide capsules, USP may elevate blood uric acid levels, which may require dosage adjustments of antigout medications to manage hyperuricemia and gout.

Lithium should generally not be administered with diuretics, as they can reduce renal clearance and increase the risk of lithium toxicity. It is advisable to consult circulars for lithium preparations before considering concomitant therapy with triamterene and hydrochlorothiazide capsules, USP.

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

Chronic or excessive use of laxatives may lead to reduced serum potassium levels by promoting potassium loss from the intestinal 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.

Laboratory Test Interactions

Triamterene and quinidine share similar fluorescence spectra, which may interfere with the fluorescent measurement of quinidine when both are administered together.

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 this lack of established safety and efficacy when making treatment decisions for pediatric patients.

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 triamterene and hydrochlorothiazide capsules, USP to this population.

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 medications. Consequently, careful monitoring of renal function is warranted in geriatric patients, particularly those with known renal impairment.

Periodic assessments of blood urea nitrogen (BUN) and serum creatinine levels should be conducted to ensure the safety and efficacy of treatment in elderly patients, especially those with suspected or confirmed renal insufficiency. Adjustments to dosage may be necessary based on these evaluations to mitigate the risk of adverse effects.

Pregnancy

The use of triamterene and hydrochlorothiazide capsules, USP during pregnancy is classified as Category C, indicating that the safety of these medications in pregnant patients has not been established due to the absence of adequate and well-controlled studies. Therefore, triamterene and hydrochlorothiazide capsules, USP should only be administered during pregnancy if the potential benefits justify the risks to the fetus.

Animal reproduction studies have not consistently predicted human responses, which necessitates caution when considering the use of this medication in pregnant women. It is important to note that both thiazides and triamterene can cross the placental barrier and are detectable in cord blood. Consequently, the anticipated benefits of treatment must be carefully weighed against potential hazards to the fetus.

Possible adverse effects associated with the use of these medications during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other reactions that have been observed in adult populations. Healthcare professionals should remain vigilant and consider these risks when prescribing triamterene and hydrochlorothiazide capsules, USP to women of childbearing potential.

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 of hyperkalemia when using triamterene and hydrochlorothiazide capsules, USP, particularly those with diabetes, the elderly, or those who are severely ill. It is essential to monitor serum potassium levels at frequent intervals, especially when initiating treatment, adjusting dosages, or during any illness that may affect renal function. Close monitoring is crucial to mitigate the risk of hyperkalemia in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to 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, 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

No teratogenic effects were observed in the studies conducted. Hydrochlorothiazide did not demonstrate adverse effects on the fertility of mice and rats of either sex when administered via diet at doses of up to 100 mg/kg/day for mice and 4 mg/kg/day for rats prior to mating and throughout gestation. These doses correspond to multiples of the Maximum Recommended Human Dose (MRHD) of 100 times for mice and 4 times for rats based on body weight, and 9.4 times for mice and 0.8 times for rats based on body surface area.

Long-term studies involving triamterene and hydrochlorothiazide capsules, USP, or triamterene alone have not been conducted. Two-year feeding studies performed under the National Toxicology Program (NTP) evaluated the effects of hydrochlorothiazide in mice and rats at doses of up to 600 mg/kg/day and 100 mg/kg/day, respectively. These doses represent 600 times the MRHD for hydrochlorothiazide in mice and 100 times in rats based on body weight, and 56 times in mice and 21 times in rats based on body surface area. The studies revealed no evidence of carcinogenic potential in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice.

No studies have been conducted to assess the mutagenic potential of triamterene and hydrochlorothiazide capsules, USP, or triamterene alone. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, as well as in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations and in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. 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 observed in the Aspergillus nidulans nondisjunction assay at an unspecified concentration of hydrochlorothiazide.

Studies evaluating the effects of triamterene and hydrochlorothiazide capsules, USP, or triamterene alone on animal reproductive function have not been conducted.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Hyperkalemia has been noted in diabetic patients using potassium-sparing agents, even in the absence of apparent renal impairment. Additionally, cases of acute renal failure, including one instance of irreversible renal failure, have been documented. Reports of renal stones primarily composed of triamterene have also been received.

Hypersensitivity reactions have been observed, including anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, and photosensitivity.

Other adverse reactions reported encompass a wide range of conditions, such as arrhythmia, postural hypotension, diabetes mellitus, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, hypochloremia, jaundice and/or liver enzyme abnormalities, and pancreatitis. Gastrointestinal disturbances, including nausea and vomiting, diarrhea, constipation, and abdominal pain, have also been noted. Hematological effects such as leukopenia, thrombocytopenia, purpura, megaloblastic anemia, and aplastic anemia have been reported, alongside symptoms like muscle cramps, weakness, fatigue, dizziness, headache, dry mouth, impotence, sialadenitis, paresthesias, and vertigo.

Serious adverse events include allergic pneumonitis, pulmonary edema, respiratory distress, necrotizing vasculitis, exacerbation of lupus, hemolytic anemia, and agranulocytosis. Notably, cases of pancreatitis in neonates and infants whose mothers received thiazides during pregnancy have been documented. Severe skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have also been reported.

Patient Counseling

Patients should be advised to monitor their serum potassium levels regularly, particularly when initiating treatment or adjusting dosages. It is important for patients to recognize the warning signs of hyperkalemia, which include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock, and to seek medical attention if these symptoms occur.

Patients must be informed that triamterene and hydrochlorothiazide capsules are contraindicated for individuals who are taking other potassium-sparing agents or potassium-containing salt substitutes. Potassium supplementation should only be considered in severe cases of hypokalemia and requires careful monitoring of serum potassium levels.

For patients with diabetes, it is essential to caution that thiazides may induce hyperglycemia and alter insulin requirements. Patients should also be advised to report any symptoms indicative of acute myopia or angle-closure glaucoma, such as decreased visual acuity or ocular pain, as these may arise with the use of hydrochlorothiazide.

It is critical to inform patients that the use of diuretics in otherwise healthy pregnant women is inappropriate and may pose unnecessary risks to both the mother and fetus. Patients should be instructed to contact their healthcare provider if they experience symptoms of electrolyte imbalance, which may include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, or gastrointestinal symptoms.

Patients should avoid the use of nonsteroidal anti-inflammatory drugs (NSAIDs) while taking triamterene and hydrochlorothiazide capsules due to the potential risk of acute renal failure. Additionally, it is important to inform patients that thiazides may decrease arterial responsiveness to norepinephrine and could enhance the paralyzing effect of nondepolarizing muscle relaxants during surgical procedures.

Finally, patients should be advised to maintain adequate hydration and to report any signs of dehydration or excessive fluid loss to their healthcare provider.

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

Laboratory tests are essential for monitoring patients on triamterene and hydrochlorothiazide capsules, USP. Clinicians should regularly assess serum potassium levels, which normally range from 3.5 to 5.0 mEq per liter, with 4.5 mEq often used as a reference. If hypokalemia occurs, potassium supplementation or dietary adjustments should be implemented cautiously, with frequent monitoring. Persistent hyperkalemia (levels above 6 mEq per liter) necessitates careful observation and potential treatment adjustments, including discontinuation of the medication if necessary.

Additionally, triamterene and hydrochlorothiazide may elevate blood urea nitrogen (BUN) and creatinine levels due to reversible reductions in glomerular filtration rate or intravascular fluid volume depletion, rather than renal toxicity. These levels typically normalize upon discontinuation of the medication. Periodic monitoring of BUN and serum creatinine is particularly important in elderly patients and those with renal insufficiency. Thiazides can also lower serum protein-bound iodine (PBI) levels without indicating thyroid dysfunction, and should be stopped prior to parathyroid function tests due to their effect on calcium excretion. While some patients on prolonged thiazide therapy have shown pathologic changes in parathyroid glands, common complications of hyperparathyroidism have not been observed.

FDA Insert (PDF)

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

View full prescribing information (PDF)