Triamterene/Hydrochlorothiazide

Description

Each Triamterene and hydrochlorothiazide capsule, USP, for oral use, features an opaque red cap and an opaque white body. Each capsule contains 25 mg of hydrochlorothiazide and 37.5 mg of triamterene, imprinted with "T 49" in black ink. Hydrochlorothiazide serves as a diuretic and antihypertensive agent, while triamterene functions as an antikaliuretic agent.

Hydrochlorothiazide, with a chemical structure of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, is slightly soluble in water and soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide. It is sparingly soluble in methanol. In contrast, triamterene, identified as 2,4,7-triamino-6-phenylpteridine, is practically insoluble in water at 50°C (less than 0.1%) and is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in alcohol.

Inactive ingredients in the formulation include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, cetylpyridinium chloride, povidone, polysorbate 80, glycine, and magnesium stearate. The capsule shells are composed of gelatin, D&C Red No. 33, FD&C Yellow No. 6, and titanium dioxide. The black ink used for imprinting contains shellac, propylene glycol, black iron oxide (E172), and potassium hydroxide.

Uses and Indications

This fixed combination drug is indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone. It is also indicated for patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked. The drug may be used alone or as an adjunct to other antihypertensive agents, such as beta-blockers; however, dosage adjustments may be necessary due to the potential enhancement of these agents' effects.

This drug is not indicated for the initial therapy of edema or hypertension except in individuals where the risk of developing hypokalemia is unacceptable.

Limitations of Use The routine use of diuretics in otherwise healthy pregnant women is inappropriate and poses unnecessary risks to both mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating established toxemia. While hypervolemia during normal pregnancy is generally not harmful, it is associated with edema in many pregnant women.

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 non-pharmacological means, such as elevation of the lower extremities and the use of support hose. In rare cases where edema causes significant discomfort not alleviated by rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dose of Triamterene and hydrochlorothiazide capsules, USP, is 1 or 2 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 are contraindicated in patients receiving other potassium-sparing agents, including spironolactone, amiloride, or other formulations containing triamterene, due to the risk of hyperkalemia. The use of concomitant potassium-containing salt substitutes is also contraindicated. Potassium supplementation should be avoided except in severe cases of hypokalemia.

This combination is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment, as these conditions may exacerbate renal function. Additionally, hypersensitivity to either drug in the formulation or to other sulfonamide-derived drugs is a contraindication. Finally, the use of triamterene and hydrochlorothiazide is contraindicated in patients with pre-existing elevated serum potassium levels.

Warnings and Precautions

Hyperkalemia is a significant risk associated with the use of potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide. An abnormal elevation of serum potassium levels (≥ 5.5 mEq/liter) can occur, particularly in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or those who are severely ill. It is imperative that serum potassium levels are monitored at frequent intervals, especially in patients initiating therapy with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of any illness that may affect renal function.

In cases where hyperkalemia is suspected—indicated by symptoms such as paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, or shock—an electrocardiogram (ECG) should be performed immediately. Should hyperkalemia be confirmed, the administration of triamterene and hydrochlorothiazide capsules must be discontinued without delay, and a thiazide diuretic alone should be considered as a substitute. If serum potassium levels exceed 6.5 mEq/L, more aggressive treatment is warranted, which may include intravenous calcium chloride, sodium bicarbonate, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. In certain cases, cationic exchange resins such as sodium polystyrene sulfonate may be administered orally or rectally. Persistent hyperkalemia may necessitate dialysis. It is crucial to note that the risk of developing hyperkalemia is heightened in patients with renal impairment, and those with mild renal functional impairment should not receive this medication without continuous monitoring of serum electrolytes. Cumulative drug effects may also be observed in patients with impaired renal function, and serum electrolytes must be frequently monitored in diabetic patients receiving this therapy.

In addition to hyperkalemia, the potential for metabolic or respiratory acidosis exists. Potassium-sparing therapy should be avoided in severely ill patients who may be at risk for these conditions. Regular evaluations of acid/base balance and serum electrolytes are essential when employing triamterene and hydrochlorothiazide.

Furthermore, hydrochlorothiazide has been associated with an idiosyncratic reaction that can lead to acute transient myopia and secondary angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically manifesting within hours to weeks following the initiation of treatment. The primary course of action is to discontinue hydrochlorothiazide as swiftly as possible. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma and should be monitored closely.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, and photosensitivity. Cardiovascular events 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, 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, vomiting, diarrhea, constipation, and abdominal pain. Metabolic abnormalities may occur, including diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia. Central nervous system effects may include weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo. Musculoskeletal symptoms such as muscle cramps have also been reported.

Ophthalmic reactions may involve xanthopsia and transient blurred vision. Skin reactions can include erythema multiforme, including Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis. Miscellaneous reactions such as impotence, sialadenitis, necrotizing vasculitis, and exacerbation of lupus have been observed. 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 in the population is approximately 1 additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥50,000 mg, the risk increases to approximately 1 additional case for every 6,700 patients per year.

Monitoring for hyperkalemia is essential, as abnormal elevations in serum potassium levels (≥5.5 mEq/liter) can occur, particularly in patients with renal impairment, diabetes, the elderly, or those who are severely ill. Uncorrected hyperkalemia may be fatal. Additionally, potassium-sparing therapy should be avoided in severely ill patients at risk for respiratory or metabolic acidosis. Hydrochlorothiazide may also cause acute myopia and secondary angle-closure glaucoma, with symptoms typically occurring within hours to weeks of initiation.

Drug Interactions

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

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

There have been reports of acute renal failure in patients receiving indomethacin, a nonsteroidal anti-inflammatory agent, alongside triamterene and hydrochlorothiazide capsules. Caution is warranted when administering nonsteroidal anti-inflammatory agents with this combination.

Lithium should generally be avoided in patients taking diuretics, as these agents can reduce lithium's renal clearance, increasing the risk of lithium toxicity. It is essential to consult the prescribing information for lithium preparations before considering concomitant therapy with triamterene and hydrochlorothiazide.

Thiazide diuretics have been shown to decrease arterial responsiveness to norepinephrine, attributed to sodium loss; however, this effect does not compromise the therapeutic efficacy of norepinephrine as a pressor agent.

Additionally, thiazides may enhance the paralyzing effects of nondepolarizing muscle relaxants, such as tubocurarine, due to potassium loss. Caution should be exercised in patients undergoing surgical procedures.

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.

Oral anticoagulants may have diminished effectiveness when used concurrently with hydrochlorothiazide, necessitating potential dosage adjustments.

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

Certain agents, when administered alongside triamterene, may lead to serum potassium accumulation, increasing the risk of 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. 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 intestinal tract, potentially interfering with the potassium-retaining effects of triamterene.

Triamterene and quinidine share similar fluorescence spectra, which may interfere with the fluorescent measurement of quinidine when both are present. Caution is advised in interpreting quinidine levels in the presence of triamterene and hydrochlorothiazide.

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 if they have renal impairment or diabetes, or if they are severely ill. Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced in this population, leading to elevated plasma levels following administration of triamterene and hydrochlorothiazide capsules.

Due to these considerations, 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 medication is not recommended without frequent and ongoing monitoring of serum electrolytes to ensure patient safety and mitigate potential adverse effects.

Pregnancy

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. These capsules should only be administered during pregnancy if the potential benefits justify the risks to the fetus.

Both triamterene and hydrochlorothiazide have been shown to cross the placental barrier and can be detected in cord blood. Therefore, the use of these medications in pregnant patients necessitates careful consideration of the anticipated benefits against potential hazards to the fetus. Possible risks associated with the use of thiazides and triamterene during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been observed in adults.

Given that animal reproduction studies do not always predict human responses, healthcare professionals should exercise caution and only prescribe triamterene and hydrochlorothiazide capsules during pregnancy when clearly needed. There are no adequate and well-controlled studies available for hydrochlorothiazide in pregnant women, further emphasizing the need for careful risk assessment in this population.

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 for hyperkalemia, particularly those with diabetes, the elderly, or those who are severely ill, even in the absence of overt renal dysfunction. Serum potassium levels should be monitored at frequent intervals, especially when initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or in the presence of any illness that may affect renal function.

The risk of hyperkalemia associated with potassium-sparing diuretics is heightened in patients with renal impairment. Therefore, patients with mild renal functional impairment should not receive this medication without close and ongoing monitoring of serum electrolytes. Cumulative drug effects may occur in individuals with impaired renal function, as evidenced by reduced renal clearances of hydrochlorothiazide and the active metabolite of triamterene, leading to increased plasma levels in elderly patients and those with renal impairment.

In diabetic patients, serum electrolytes must be frequently monitored when using triamterene and hydrochlorothiazide capsules. Additionally, potassium-sparing therapy should be avoided in severely ill patients who may experience respiratory or metabolic acidosis. If triamterene and hydrochlorothiazide is prescribed, regular evaluations of acid/base balance and serum electrolytes are essential.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established 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

Electrolyte imbalance is the primary concern associated with overdosage. Symptoms that may manifest include polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes.

In the event of hypotension, treatment 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 management.

Immediate intervention is necessary; therefore, the induction of gastric evacuation should be performed through emesis or gastric lavage. It is important to note that there is no specific antidote available for this overdosage.

Reports have indicated that reversible acute renal failure can occur following the ingestion of 50 tablets of a product containing 50 mg of triamterene and 25 mg of hydrochlorothiazide. While triamterene is predominantly protein-bound (approximately 67%), there may 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 the triamterene and hydrochlorothiazide capsule 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 conducted in rats at doses up to 20 times the MRHD based on body weight and 6 times the human dose based on body surface area, with no evidence of fetal harm. Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses of up to 3,000 mg/kg/day for mice and 1,000 mg/kg/day for rats. These doses 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 safety of triamterene and hydrochlorothiazide, either as a combination or individually, 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 correspond to 600 times and 100 times the MRHD for hydrochlorothiazide at 50 mg/day (or 1.0 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.

Studies assessing the mutagenic potential of the triamterene and hydrochlorothiazide combination or triamterene alone have not been performed. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test with Salmonella typhimurium strains and tests for chromosomal aberrations in Chinese Hamster Ovary (CHO) cells. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and the mouse Lymphoma Cell mutagenicity assays at 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.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these animals were exposed to doses of up to 100 mg/kg/day for mice and 4 mg/kg/day for rats prior to mating and throughout gestation. These doses correspond to 100 times the MRHD for mice and 4 times the MRHD for rats based on body weight, and 9.4 times and 0.8 times the MRHD based on body surface area, respectively.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer. Data from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed for squamous cell carcinoma (SCC), particularly among white patients who have received large cumulative doses of the medication. Specifically, the overall population exhibits an increased risk of approximately one additional case of SCC per 16,000 patients per year. In white patients who have taken a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing, using sunscreen with a high SPF, and avoiding prolonged sun exposure, especially during peak hours.

Additionally, healthcare providers should emphasize the importance of regular skin cancer screenings for patients on this medication. Patients should be made aware of the signs of skin changes and encouraged to report any unusual skin lesions or changes to their healthcare provider promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container to ensure its integrity and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to maintain its quality.

Additional Clinical Information

Serum potassium levels in patients 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 are recommended, with careful monitoring of serum potassium levels. Persistent elevations above 6 mEq/L necessitate close observation and treatment, and any corrective measures should be halted if serum potassium levels rise abnormally. 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, particularly in elderly patients or those with renal insufficiency. Regular monitoring of BUN and serum creatinine is advised, and thiazides should be discontinued prior to parathyroid function tests due to their effect on calcium excretion.

Clinicians should counsel patients taking hydrochlorothiazide to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an associated increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). This risk is notably higher in white patients receiving large cumulative doses, with an estimated increase of one additional SCC case per 6,700 patients per year for those taking ≥50,000 mg.

FDA Insert (PDF)

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

View full prescribing information (PDF)