Triamterene/Hydrochlorothiazide

Description

Each triamterene and hydrochlorothiazide 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 chemical name 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74. It exhibits slight solubility in water and is soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide, while being sparingly soluble in methanol.

Triamterene, an antikaliuretic agent, is identified by the chemical name 2,4,7-triamino-6-phenylpteridine, with a molecular formula of C12H11N7 and a molecular weight of 253.26. At 50°C, triamterene is practically insoluble in water (less than 0.1%) but is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in alcohol.

The formulation includes inactive ingredients such as 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 imprinting ink consists of 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

This fixed combination drug is indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide alone. It is not indicated for the initial therapy of edema or hypertension except in individuals where the risk of developing hypokalemia cannot be tolerated.

Triamterene and hydrochlorothiazide capsules, USP may be utilized as a standalone treatment or in conjunction with other antihypertensive agents, such as beta-blockers. Due to the potential for enhanced effects of these agents, dosage adjustments may be necessary.

Limitations of Use The routine use of diuretics in otherwise healthy pregnant women is inappropriate, as it 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.

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 mechanical factors, such as venous return restriction due to an expanded uterus, should be managed through non-pharmacological means, including elevation of the lower extremities and the use of support hose. The hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus in the absence of cardiovascular disease, and it is often accompanied by edema. If this edema causes significant discomfort, increased recumbency may provide relief. In rare cases where extreme discomfort persists despite rest, a short course of diuretics may be appropriate.

Dosage and Administration

The usual dose of triamterene and hydrochlorothiazide capsules, 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 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, concomitant use of potassium-containing salt substitutes is prohibited.

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, serum potassium levels must be closely monitored.

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.

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

Lastly, this medication should not be administered to patients with pre-existing elevated serum potassium levels, as it may further increase potassium concentrations.

Warnings and Precautions

Abnormal elevation of serum potassium levels (≥5.5 mEq/liter) can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide capsules, USP. The risk of hyperkalemia is heightened in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or those who are severely ill. Given that uncorrected hyperkalemia may be fatal, it is imperative that serum potassium levels are monitored at frequent intervals, particularly in patients initiating treatment with triamterene and hydrochlorothiazide capsules, USP, when dosages are altered, or during any illness that may affect renal function.

In cases where hyperkalemia is suspected, characterized by symptoms such as paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock, an electrocardiogram (ECG) should be performed. It is crucial to note that hyperkalemia may not always present with ECG changes, thus ongoing monitoring of serum potassium levels is essential. Should hyperkalemia be confirmed, triamterene and hydrochlorothiazide capsules, USP must be discontinued immediately, and a thiazide diuretic should be substituted. If serum potassium levels exceed 6.5 mEq/L, more aggressive therapeutic measures are warranted, which may include intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. Cationic exchange resins, such as sodium polystyrene sulfonate, may be administered orally or rectally, and persistent hyperkalemia may necessitate dialysis.

The development of hyperkalemia is particularly pronounced in patients with renal impairment. Therefore, patients with mild renal functional impairment should not be treated with this medication without close and continuous monitoring of serum electrolytes. Cumulative drug effects may occur in individuals with impaired renal function, as evidenced by reduced renal clearance of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, leading to increased plasma levels in elderly patients and those with renal impairment.

Diabetic patients using potassium-sparing agents are also at risk for hyperkalemia, even in the absence of apparent renal impairment. Consequently, serum electrolytes must be monitored frequently in this population. Additionally, potassium-sparing therapy should be avoided in severely ill patients who may experience respiratory or metabolic acidosis, as acidosis can lead to rapid increases in serum potassium levels. If triamterene and hydrochlorothiazide capsules, USP are prescribed, regular evaluations of acid/base balance and serum electrolytes are necessary.

Hydrochlorothiazide, a sulfonamide, may induce an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment. Untreated acute angle-closure glaucoma can result in permanent vision loss. The primary course of action is to discontinue hydrochlorothiazide as swiftly as possible, and prompt medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

In summary, vigilant monitoring of serum potassium levels and ECGs is essential in patients receiving triamterene and hydrochlorothiazide capsules, USP, particularly in those with risk factors for hyperkalemia. Immediate discontinuation of the medication is required if hyperkalemia is confirmed.

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. Renal complications can manifest as acute renal failure, with one case of irreversible renal failure documented, interstitial nephritis, and renal stones primarily composed of triamterene. Hematologic issues may include leukopenia, thrombocytopenia with purpura, megaloblastic anemia, aplastic anemia, agranulocytosis, and hemolytic anemia. Additionally, respiratory complications such as allergic pneumonitis, pulmonary edema, and respiratory distress have been observed.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation, abdominal pain, and jaundice or liver enzyme abnormalities. Metabolic changes may involve 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 such as muscle cramps have also been noted.

Ophthalmic reactions may present as xanthopsia and transient blurred vision. Skin reactions can be severe, including erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis. Miscellaneous reactions such as impotence, sialadenitis, necrotizing vasculitis, and exacerbation of lupus have been reported. In neonates and infants, rare cases of thrombocytopenia and pancreatitis have been observed in newborns whose mothers received thiazides during pregnancy.

Postmarketing experience has indicated 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 was approximately one additional case per 16,000 patients per year, while for white patients receiving a cumulative dose of ≥50,000 mg, the risk increased to approximately one additional case for every 6,700 patients per year.

Monitoring for hyperkalemia is critical, 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, necessitating frequent serum potassium level assessments, especially when initiating treatment or adjusting dosages.

Drug Interactions

Concurrent use of certain drug classes with triamterene and hydrochlorothiazide capsules, USP may lead to significant interactions that require careful consideration.

Angiotensin-Converting Enzyme Inhibitors Potassium-sparing agents, including triamterene, should be used with caution alongside angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia. Monitoring of serum potassium levels is advised.

Oral Hypoglycemic Drugs The combination of chlorpropamide with oral hypoglycemic agents may elevate the risk of severe hyponatremia. Close monitoring of sodium levels is recommended.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Caution is warranted when administering NSAIDs, such as indomethacin, in patients taking triamterene and hydrochlorothiazide capsules, USP, as this combination has been associated with acute renal failure in some cases. Monitoring of renal function is advisable.

Lithium The use of diuretics, including triamterene and hydrochlorothiazide capsules, USP, is generally contraindicated with lithium due to the potential for reduced renal clearance and increased risk of lithium toxicity. Review prescribing information for lithium preparations prior to concurrent therapy.

Surgical Considerations Thiazides may diminish arterial responsiveness to norepinephrine, although this effect does not negate the therapeutic efficacy of pressor agents. Additionally, thiazides can enhance the neuromuscular blocking effects of nondepolarizing muscle relaxants, such as tubocurarine. Caution is advised in surgical patients.

Electrolyte Imbalance Concurrent use of hydrochlorothiazide with amphotericin B, corticosteroids, or corticotropin (ACTH) may exacerbate electrolyte imbalances, particularly hypokalemia. However, the presence of triamterene may mitigate this effect. Monitoring of electrolyte levels is recommended.

Oral Anticoagulants Hydrochlorothiazide may reduce the effectiveness of oral anticoagulants, necessitating potential dosage adjustments. Regular monitoring of coagulation parameters is advised.

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

Potassium Accumulation The following agents may promote serum potassium accumulation when used with triamterene, increasing the risk of hyperkalemia, particularly in patients with renal insufficiency: blood products (which may contain significant potassium levels), low-salt milk, potassium-containing medications (e.g., parenteral penicillin G potassium), and salt substitutes. Monitoring of serum potassium levels is essential.

Exchange Resins Sodium polystyrene sulfonate, whether administered orally or rectally, can lower serum potassium levels through sodium replacement. However, fluid retention may occur due to increased sodium intake.

Laxatives Chronic or excessive use of laxatives may lead to reduced serum potassium levels by promoting excessive potassium loss from the gastrointestinal tract, potentially interfering with the potassium-retaining effects of triamterene.

Methenamine The effectiveness of methenamine may be diminished when used concurrently with hydrochlorothiazide due to the alkalinization of urine. Monitoring of therapeutic efficacy is recommended.

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. It is important for healthcare providers to monitor these patients closely due to their heightened vulnerability.

Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, the sulfate ester of hydroxytriamterene, are significantly reduced in elderly patients. Consequently, plasma levels of these medications may be elevated following administration of triamterene and hydrochlorothiazide capsules, USP.

To ensure patient safety, periodic assessments of blood urea nitrogen (BUN) or serum creatinine levels are recommended, particularly for elderly patients and those with suspected or confirmed renal insufficiency. This monitoring is crucial to mitigate the risks associated with potential renal impairment and to adjust dosages as necessary.

Pregnancy

The safe use of triamterene and hydrochlorothiazide capsules, USP during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women. Therefore, these capsules should be administered during pregnancy only if the potential benefit justifies the risk to the fetus.

Animal reproduction studies are not always predictive of human response; thus, the use of this medication in pregnant patients should be approached with caution and only if clearly needed. It is important to note that both thiazides and triamterene have been shown to cross the placental barrier and can be detected in cord blood.

Healthcare professionals should carefully weigh the anticipated benefits against the possible hazards to the fetus when considering the use of triamterene and hydrochlorothiazide capsules, USP in pregnant women. Potential risks include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and other adverse reactions that have been observed in adults.

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 similar excretion may occur in humans. Additionally, thiazides are known to be excreted in human breast milk.

If the use of this combination drug product is deemed essential, it is recommended that the lactating mother discontinue breastfeeding.

Renal Impairment

Patients with renal impairment may experience abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) when using triamterene and hydrochlorothiazide capsules, USP. The risk of hyperkalemia is heightened in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or those who are severely ill.

Serum potassium levels must be monitored at frequent intervals, particularly in patients initiating treatment with triamterene and hydrochlorothiazide capsules, USP, when dosages are adjusted, or during any illness that may affect renal function. The development of hyperkalemia associated with potassium-sparing diuretics is exacerbated in the presence of renal impairment.

Patients with mild renal functional impairment should not receive this medication without ongoing and frequent monitoring of serum electrolytes. Cumulative drug effects may occur in patients with impaired renal function, as evidenced by reduced renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, leading to increased plasma levels in elderly patients and those with renal impairment.

In diabetic patients, serum electrolytes must be closely monitored if triamterene and hydrochlorothiazide capsules, USP are prescribed. Additionally, potassium-sparing therapy should be avoided in severely ill patients at risk for respiratory or metabolic acidosis. If these capsules are used, frequent 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

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.

Nonclinical Toxicology

Animal reproduction studies to evaluate the potential for fetal harm associated with triamterene and hydrochlorothiazide capsules, USP have not been conducted. However, a One Generation Study in rats approximating the composition of these capsules, using a 1:1 ratio of triamterene to hydrochlorothiazide at doses of 30 mg/kg/day each, demonstrated no evidence of teratogenicity. 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, USP during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women. Therefore, these capsules should be administered during pregnancy only if the potential benefit justifies the risk to the fetus.

Reproduction studies in rats at doses up to 20 times the MRHD based on body weight and 6 times the human dose based on body surface area revealed no evidence of fetal harm due to triamterene. 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. At these doses, which are multiples of the MRHD equal to 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, no evidence of fetal harm was observed. However, due to the limitations of animal reproduction studies in predicting human responses, the use of this drug during pregnancy should be considered only when clearly necessary.

Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of these agents 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 observed in adults.

Long-term studies with triamterene and hydrochlorothiazide capsules, USP or with triamterene alone have not been conducted. Two-year feeding studies in mice and rats, conducted under the National Toxicology Program (NTP), administered hydrochlorothiazide at doses up to 600 mg/kg/day in mice and 100 mg/kg/day in rats. These doses represent 600 times and 100 times the MRHD for hydrochlorothiazide at 50 mg/day based on body weight, and 56 times and 21 times the MRHD based on body surface area, respectively. These studies did not reveal evidence of carcinogenic potential for hydrochlorothiazide in rats or female mice, although equivocal evidence of hepatocarcinogenicity was noted in male mice.

Studies assessing the mutagenic potential of triamterene and hydrochlorothiazide capsules, USP or of triamterene alone have not been performed. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test and tests for chromosomal aberrations. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange test and in mouse Lymphoma Cell assays at concentrations ranging from 43 to 1,300 mcg/mL. Additionally, positive results were noted in the Aspergillus nidulans nondisjunction assay.

Investigations into the effects of triamterene and hydrochlorothiazide capsules, USP or of 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 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. These doses correspond to 100 times and 4 times the MRHD based on body weight, and 9.4 times and 0.8 times the MRHD based on body surface area, respectively.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, as reported in postmarketing surveillance. Data from a study conducted within the Sentinel System indicate that the elevated risk is primarily linked to squamous cell carcinoma (SCC), particularly among white patients receiving large cumulative doses of the medication. The overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. Notably, for white patients who have taken a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 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 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

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. It is important to note that serum potassium levels may not accurately reflect total body potassium concentration, and a rise in plasma pH can affect potassium distribution. In cases of abnormal serum potassium elevation, corrective measures should be halted, and triamterene and hydrochlorothiazide capsules should be discontinued until potassium levels normalize.

Clinicians should also be aware that triamterene and hydrochlorothiazide capsules 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. Regular monitoring of BUN and serum creatinine is advised, particularly in elderly patients or those with renal insufficiency. Additionally, thiazides can lower serum protein-bound iodine levels without causing thyroid dysfunction, and they should be discontinued prior to parathyroid function tests due to their effect on calcium excretion. Patients on prolonged thiazide therapy have shown pathologic changes in parathyroid glands, although common complications of hyperparathyroidism have not been observed.

Patients taking hydrochlorothiazide should be counseled on the increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving high cumulative doses. Regular skin cancer screenings and sun protection measures are recommended. The risk of SCC in the general population is approximately 1 additional case per 16,000 patients per year, increasing to 1 additional case for every 6,700 patients per year in those taking a cumulative dose of ≥50,000 mg.

FDA Insert (PDF)

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

View full prescribing information (PDF)