Triamterene/Hydrochlorothiazide

Description

Each capsule of triamterene and hydrochlorothiazide for oral administration contains 37.5 mg of triamterene, a potassium-sparing diuretic, and 25 mg of hydrochlorothiazide, a thiazide diuretic and antihypertensive agent. The capsules are characterized by an opaque yellow cap and an opaque white body, imprinted with the code 855.

Hydrochlorothiazide, with the chemical designation 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, exhibits very slight solubility in water and is 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.

Triamterene, identified as 2,4,7-triamino-6-phenylpteridine, is soluble in formic acid and sparingly soluble in methoxyethanol. It shows very slight solubility in acetic acid, alcohol, and dilute mineral acids, while being 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 the 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 minimized.

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 potentiate 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 onset 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 attributable 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 non-pharmacological means, such as elevating the lower extremities and utilizing support hose. The use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary.

It is acknowledged that hypervolemia is a normal physiological condition during pregnancy, which does not adversely affect the mother or fetus in the absence of cardiovascular disease, despite being associated with edema. For cases where edema causes significant discomfort and is unresponsive to increased recumbency, 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:

• Use is contraindicated in patients receiving other potassium-sparing agents, including spironolactone, amiloride, or other formulations containing triamterene, due to the risk of hyperkalemia.

• Concomitant use of potassium-containing salt substitutes is prohibited to prevent elevated serum potassium levels.

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

• The capsules are contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the risk of further renal compromise.

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

• The use of these capsules is not recommended in patients with pre-existing elevated serum potassium, as it may exacerbate the condition.

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 interfere with 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 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. Additionally, hematologic issues such as leukopenia, thrombocytopenia, purpura, megaloblastic anemia, aplastic anemia, agranulocytosis, and hemolytic anemia have been observed.

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 may present as weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo. Musculoskeletal symptoms such as muscle cramps have also been reported.

Ophthalmic reactions may include xanthopsia and transient blurred vision, while respiratory issues can manifest as allergic pneumonitis, pulmonary edema, and respiratory distress. Miscellaneous adverse reactions include impotence, sialadenitis, necrotizing vasculitis, and exacerbation of lupus.

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

Postmarketing experience has indicated 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.

A boxed warning highlights the risk of hyperkalemia, defined as an abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter), which can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide capsules. Hyperkalemia is more likely in patients with renal impairment, diabetes (even without evidence of renal impairment), and in the elderly or severely ill. Uncorrected hyperkalemia may be fatal; therefore, serum potassium levels must be monitored frequently, especially in patients initiating treatment with triamterene and hydrochlorothiazide capsules, when dosages are adjusted, 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 triamterene and hydrochlorothiazide capsules with chlorpropamide may increase the risk of severe hyponatremia. Close monitoring of sodium levels is advised.

Caution is warranted when administering nonsteroidal anti-inflammatory agents, such as indomethacin, to patients on triamterene and hydrochlorothiazide capsules, as a few cases of acute renal failure have been reported with this combination.

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

Thiazide diuretics, including hydrochlorothiazide, may decrease arterial responsiveness to norepinephrine, although this effect does not preclude the therapeutic use of norepinephrine. Additionally, thiazides can enhance the paralyzing effects of nondepolarizing muscle relaxants, such as tubocurarine, necessitating caution in patients undergoing surgical procedures.

The concurrent use 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 effectiveness of oral anticoagulants may be diminished when used concurrently with hydrochlorothiazide, and dosage adjustments may be required based on clinical response.

Triamterene and hydrochlorothiazide may elevate blood uric acid levels, which could necessitate dosage adjustments 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 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, but may also lead to fluid retention due to increased sodium intake.

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 concurrent use of hydrochlorothiazide may reduce the effectiveness of methenamine due to urine alkalinization, which should be considered when prescribing these medications 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 the potential risks and benefits before prescribing this medication to 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. Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, hydroxytriamterene sulfate, are significantly reduced in this population. Consequently, plasma levels of these medications may be elevated following administration to elderly patients or those with compromised renal function.

Due to these considerations, it is essential to conduct periodic assessments of blood urea nitrogen (BUN) and serum creatinine levels in elderly patients, particularly in those with suspected or confirmed renal insufficiency. Monitoring these parameters can help mitigate the risk of adverse effects and ensure safe and effective use of the medication in geriatric patients.

Pregnancy

The safety of triamterene and hydrochlorothiazide capsules during pregnancy has not been established due to the absence of 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) did not show evidence of teratogenicity, even at levels significantly exceeding the maximum recommended human dose (MRHD) based on body weight and surface area.

Reproduction studies involving hydrochlorothiazide in pregnant mice and rats during critical periods of organogenesis revealed no fetal harm at high doses, which were multiples of the MRHD. Nevertheless, the potential risks associated with the use of thiazides and triamterene during pregnancy must be carefully considered. These medications are known to cross the placental barrier and can be detected in cord blood. Potential hazards to the fetus include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions observed in adults.

Given the lack of definitive human data and the potential for serious fetal effects, triamterene and hydrochlorothiazide capsules should only be used during pregnancy if the anticipated benefits justify the risks to the fetus. Healthcare providers are advised to weigh these factors carefully when considering treatment options for pregnant patients or 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 it is possible that 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 further heightened in patients with diabetes, even in the absence of renal impairment, as well as in elderly or severely ill individuals.

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

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage, 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. Although triamterene is predominantly protein-bound (approximately 67%), there may be some benefit to dialysis in cases of significant overdosage. Continuous monitoring and supportive care are essential in managing the patient's condition effectively.

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 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, revealing 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, conducted 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 found 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 observed in the in vitro CHO Sister Chromatid Exchange test and mouse Lymphoma Cell mutagenicity assays at hydrochlorothiazide concentrations ranging from 43 to 1,300 mcg/mL, as well as in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

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 multiples of the MRHD of 100 for mice and 4 for rats based on body weight, and 9.4 for mice and 0.8 for rats based on body surface area.

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 encouraged to report any new or unusual skin changes 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 capsules. 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 regular serum potassium assessments. Persistent elevations above 6 mEq/L require careful management, and any abnormal increase 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 lower serum protein-bound iodine (PBI) levels without causing thyroid dysfunction. Before conducting parathyroid function tests, thiazides should be discontinued, as they decrease calcium excretion, and prolonged use may lead to pathologic changes in the parathyroid glands, although 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 Zydus Lifesciences Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)