Triamterene/Hydrochlorothiazide

Description

Each capsule of triamterene and hydrochlorothiazide for oral use contains triamterene 37.5 mg and hydrochlorothiazide 25 mg. Hydrochlorothiazide, USP is very slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethyl formamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. The chemical structure of hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Triamterene, USP is soluble in formic acid and sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol, and dilute mineral acids, and is practically insoluble in water, benzene, ether, chloroform, and dilute alkali hydroxides. The chemical structure of triamterene is 2,4,7-triamino-6-phenylpteridine. Each capsule also contains the following inactive ingredients: citric acid monohydrate, colloidal silicon dioxide, croscarmellose sodium, gelatin, glycine, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and titanium dioxide.

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. This combination is also suitable for patients requiring a thiazide diuretic where the risk of hypokalemia must be avoided.

These capsules may be administered alone or as an adjunct to other antihypertensive agents, such as beta-blockers. It is important to note that the use of triamterene and hydrochlorothiazide 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 physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there are no underlying cardiovascular issues.

In cases where edema causes significant discomfort and is unresponsive to 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 contraindicated to prevent elevated serum potassium levels.

• Potassium supplementation is contraindicated except in severe cases of hypokalemia, as it may lead to hyperkalemia.

• Patients with anuria, acute or chronic renal insufficiency, or significant renal impairment should not use this medication due to the risk of further renal compromise.

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

• Patients with pre-existing elevated serum potassium should not use these capsules to avoid exacerbating hyperkalemia.

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 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 while using this medication, which can be 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 effects may manifest as arrhythmia and postural hypotension. Renal complications can include acute renal failure, with one reported case of irreversible renal failure, interstitial nephritis, and renal stones primarily composed of triamterene. Hematologic reactions may present as leukopenia, thrombocytopenia with purpura, megaloblastic anemia, aplastic anemia, agranulocytosis, and hemolytic anemia. Additionally, respiratory issues such as allergic pneumonitis, pulmonary edema, and respiratory distress have been noted.

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

Postmarketing data indicate an association between hydrochlorothiazide and 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, with an increased risk of one additional case for every 6,700 patients per year among white patients receiving a cumulative dose of ≥50,000 mg.

It is important to monitor serum potassium levels, as hyperkalemia (serum potassium levels ≥5.5 mEq/liter) can occur with potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide. This risk is heightened 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 during any illness that may affect renal function.

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. Monitoring of serum potassium levels is recommended in patients receiving this combination.

The concurrent use of chlorpropamide may increase the risk of severe hyponatremia. Patients should be monitored for signs and symptoms of hyponatremia and electrolyte imbalances.

A potential interaction resulting in acute renal failure has been reported in patients taking triamterene and hydrochlorothiazide capsules when treated with indomethacin. Close monitoring of renal function is advised in patients receiving this combination.

Lithium should generally not be administered with diuretics, as diuretics can reduce renal clearance of lithium and increase the risk of lithium toxicity. Regular monitoring of lithium levels is recommended.

Thiazide diuretics have been shown to decrease arterial responsiveness to norepinephrine, which may have implications for surgical outcomes. Careful consideration should be given to the timing of thiazide administration in the perioperative setting.

Concurrent use of hydrochlorothiazide with amphotericin B or corticosteroids may intensify electrolyte imbalances, particularly hypokalemia. Monitoring of serum electrolytes is advised.

The effectiveness of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; therefore, dosage adjustments may be necessary based on coagulation parameters.

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

Blood products from the blood bank may contain potassium, which can lead to serum potassium accumulation when administered with triamterene. Monitoring of serum potassium levels is recommended in these patients.

Chronic or excessive use of laxatives may lead to reduced serum potassium levels due to increased potassium loss from the intestinal tract. Patients should be monitored for signs of hypokalemia.

The effectiveness of methenamine may be diminished when used concurrently with hydrochlorothiazide due to the alkalinization of urine. Consideration should be given to alternative therapies if methenamine is indicated.

Packaging & NDC

The table below lists all NDC Code configurations of Triamterene and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

Elderly patients, particularly those aged 65 and older, are at an increased risk for hyperkalemia, especially in the presence of renal impairment or diabetes, even in the absence of renal dysfunction. Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are significantly reduced in this population, leading to increased plasma levels of these medications.

Due to these pharmacokinetic changes, it is essential to conduct periodic assessments of blood urea nitrogen (BUN) or serum creatinine levels in elderly patients, particularly those with suspected or confirmed renal insufficiency. For patients with mild renal functional impairment, the use of this drug is not recommended without frequent and ongoing monitoring of serum electrolytes to mitigate the risk of adverse effects.

Healthcare providers should exercise caution when prescribing this medication to geriatric patients, ensuring appropriate dose adjustments and close monitoring to enhance safety and efficacy.

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 been conducted to assess the potential for fetal harm. However, a One Generation Study in rats demonstrated no evidence of teratogenicity at doses significantly higher than the maximum recommended human dose (MRHD). Additionally, reproduction studies with triamterene in rats at doses up to 20 times the MRHD showed no evidence of harm to the fetus. Hydrochlorothiazide has been administered to pregnant mice and rats during major organogenesis without evidence of fetal harm at high doses.

Both triamterene and hydrochlorothiazide cross the placental barrier and can be detected in cord blood. Therefore, the use of these medications in pregnant patients should be considered only if the potential benefit justifies the risk to the fetus. Possible hazards to the fetus may include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions. Healthcare professionals are advised to weigh the anticipated benefits against these potential risks when prescribing triamterene and hydrochlorothiazide capsules to women of childbearing potential.

Lactation

Thiazides and triamterene in combination have not been studied in nursing mothers. Triamterene has been shown to appear in animal milk, and this may also occur in humans. Additionally, thiazides are excreted in human breast milk. If the use of the combination drug product is deemed essential, lactating mothers should 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 particularly pronounced in those with diabetes, even in the absence of overt 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, especially during the initiation of therapy with triamterene and hydrochlorothiazide capsules, following any dosage adjustments, or in the presence of any illness that may affect renal function.

Hepatic Impairment

There is no available information 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 caution and consider the lack of data when prescribing this medication to patients with liver problems.

Overdosage

In cases of overdosage, the primary concern is the potential for electrolyte imbalance. Healthcare professionals should be vigilant for symptoms that may arise, which include polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes.

Should hypotension occur as a result of the overdose, it is recommended to administer pressor agents, such as levarterenol, to help maintain blood pressure within acceptable limits.

Immediate intervention is critical; therefore, healthcare providers should induce evacuation of the stomach through emesis or gastric lavage in instances of overdose. It is important to note that there is no specific antidote available for this condition.

Additionally, there have been reports of reversible acute renal failure following the ingestion of 50 tablets containing 50 mg of triamterene and 25 mg of hydrochlorothiazide. While triamterene is predominantly protein-bound (approximately 67%), there may still be some therapeutic benefit to dialysis in cases of overdosage.

Healthcare professionals are advised to monitor patients closely and provide supportive care as necessary.

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 (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. 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 in rats have been conducted 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 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 performed. Hydrochlorothiazide was subjected to two-year feeding studies in mice and rats under the National Toxicology Program (NTP), with doses 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 (or 1 mg/kg/day based on a 50-kg individual). The 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 TA 98, TA 100, TA 1535, TA 1537, and TA 1538, as well as in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in mouse Lymphoma Cell (mutagenicity) assays at hydrochlorothiazide concentrations ranging from 43 to 1,300 mcg/mL. Additionally, positive results were observed in the Aspergillus nidulans nondisjunction assay at an unspecified concentration of hydrochlorothiazide.

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 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 the MRHD for mice and 0.8 times the MRHD for rats based on body surface area.

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 most pronounced 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. 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.

Healthcare professionals and patients are encouraged to report any suspected adverse reactions to Viona Pharmaceuticals Inc. at 1-888-304-5011, or to the FDA at 1-800-FDA-1088 or through the website www.fda.gov/medwatch.

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

Clinicians should be aware of several important laboratory considerations when prescribing triamterene and hydrochlorothiazide. Serum potassium levels should be monitored, as the normal adult range is 3.5 to 5.0 mEq/L, with 4.5 mEq often used as a reference. If hypokalemia occurs, potassium supplementation or dietary adjustments may be necessary, but these should be implemented cautiously with frequent serum potassium assessments. Persistent levels above 6 mEq/L require careful observation and treatment, and any abnormal elevation in serum potassium should prompt immediate discontinuation of corrective measures.

Additionally, triamterene and hydrochlorothiazide may lead to elevated blood urea nitrogen (BUN) and creatinine levels due to reversible reductions in glomerular filtration rate or intravascular fluid volume depletion, rather than renal toxicity. Regular monitoring of BUN and serum creatinine is advised, particularly in elderly patients or those with renal insufficiency. Thiazides can also decrease serum protein-bound iodine levels without causing thyroid disturbances, and they should be discontinued prior to parathyroid function tests, as they reduce calcium excretion. While some patients on prolonged thiazide therapy may exhibit 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)