Triamterene/Hydrochlorothiazide

Description

Triamterene, USP is an antikaliuretic agent, while hydrochlorothiazide, USP serves as a diuretic and antihypertensive agent. Triamterene is characterized as 2,4,7-triamino-6-phenylpteridine, with a chemical formula of C12H11N7 and a molecular weight of 253.27. At 50°C, triamterene is practically insoluble in water (less than 0.1%), but it is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in alcohol. Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a chemical formula of C7H8ClN3O4S2 and a molecular weight of 297.75. Hydrochlorothiazide is slightly soluble in water and soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide, while being sparingly soluble in methanol.

Each capsule for oral administration contains 37.5 mg of triamterene, USP and 25 mg of hydrochlorothiazide, USP. The inactive ingredients in the capsule include citric acid, corn starch, glycine, anhydrous lactose, magnesium stearate, Polysorbate 80, povidone, and sodium starch glycolate. The capsule shells and imprinting inks consist of D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, FD & C Blue #2 Aluminum Lake, FD & C Red #40 Aluminum Lake, gelatin, pharmaceutical glaze, propylene glycol, synthetic black iron oxide, and titanium dioxide.

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 may be utilized as a standalone treatment or as an adjunct to other antihypertensive medications, 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 the 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 the mechanical effects of pregnancy should be managed through non-pharmacological means, such as elevating the lower extremities and using support hose. The hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there is no underlying cardiovascular disease. 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 one to two 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 are contraindicated in the following situations:

• The combination should not be administered to patients receiving other potassium-sparing agents, such as spironolactone or amiloride, or other formulations containing triamterene. The use of concomitant potassium-containing salt substitutes is also contraindicated due to the risk of hyperkalemia.

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

• The combination is contraindicated in patients with anuria, acute or chronic renal insufficiency, or significant renal impairment due to the risk of further renal deterioration.

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

• The use of triamterene and hydrochlorothiazide is contraindicated in patients with pre-existing elevated serum potassium levels, as this may exacerbate hyperkalemia.

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. Hyperkalemia is particularly likely 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, especially in patients initiating treatment with triamterene and hydrochlorothiazide, 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 must be discontinued immediately, and a thiazide diuretic alone should be substituted. If serum potassium levels exceed 6.5 mEq/L, more aggressive therapeutic measures are warranted.

The risk of developing hyperkalemia is heightened in patients with renal impairment. Therefore, patients with mild renal functional impairment should not be prescribed this combination without rigorous and continuous monitoring of serum electrolytes. Additionally, hyperkalemia has been documented in diabetic patients using potassium-sparing agents, even when renal function appears normal. Consequently, frequent monitoring of serum electrolytes is necessary for diabetic patients receiving triamterene and hydrochlorothiazide.

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 is administered in such cases, regular assessments of acid/base balance and serum electrolytes are required.

Hydrochlorothiazide, a sulfonamide, may induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically manifesting within hours to weeks of initiating treatment. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary intervention is the prompt discontinuation of hydrochlorothiazide.

Laboratory tests are essential for monitoring the safety of triamterene and hydrochlorothiazide therapy. Serum potassium levels should be regularly assessed, with the normal adult range being 3.5 to 5.0 mEq/L. Should hypokalemia occur, corrective measures such as potassium supplementation or increased dietary intake of potassium-rich foods should be implemented. Persistent potassium levels above 6 mEq/L necessitate careful observation and treatment.

Additionally, triamterene and hydrochlorothiazide may elevate blood urea nitrogen (BUN) and creatinine levels. Periodic assessments of BUN and serum creatinine are recommended, particularly in elderly patients and those with suspected or confirmed renal insufficiency. It is also advised to discontinue thiazides prior to conducting tests for parathyroid function, as thiazides decrease calcium excretion.

In the event of suspected hyperkalemia, characterized by the aforementioned warning signs, an ECG should be obtained immediately. If hyperkalemia is confirmed, triamterene and hydrochlorothiazide should be discontinued without delay, and a thiazide diuretic should be substituted.

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 occur, including 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 noted.

Patients may also experience metabolic disturbances, including diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, and hypochloremia. The boxed warning highlights the risk of hyperkalemia, defined as an abnormal elevation of serum potassium levels (≥5.5 mEq/liter), which can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide. This condition is particularly likely in patients with renal impairment, diabetes (even in the absence of renal impairment), the elderly, or those who are severely ill. Uncorrected hyperkalemia may be fatal; therefore, serum potassium levels must be monitored frequently, especially in patients initiating treatment, when dosages are adjusted, or during any illness that may affect renal function.

Common adverse reactions reported include gastrointestinal symptoms such as jaundice and/or liver enzyme abnormalities, pancreatitis, nausea and vomiting, diarrhea, constipation, and abdominal pain. Central nervous system effects may include weakness, fatigue, dizziness, headache, dry mouth, paresthesias, and vertigo. Musculoskeletal complaints such as muscle cramps and miscellaneous effects like impotence and sialadenitis have also been observed. Ophthalmic reactions may present as xanthopsia and transient blurred vision, while respiratory issues can include allergic pneumonitis, pulmonary edema, and respiratory distress.

In rare cases, skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis have been reported. Additionally, neonates and infants may experience thrombocytopenia and pancreatitis if their mothers received thiazides during pregnancy. Other serious reactions include necrotizing vasculitis and exacerbation of lupus.

Overall, careful monitoring and management of these adverse reactions are essential for patient safety.

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 dosage adjustments may be necessary.

A possible interaction resulting in acute renal failure has been reported in a few patients taking triamterene and hydrochlorothiazide when treated with indomethacin. Caution is advised when these medications are used together, and renal function should be monitored.

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

The concurrent use of hydrochlorothiazide with amphotericin B or corticosteroids may intensify electrolyte imbalances, particularly hypokalemia. Patients should be monitored for electrolyte levels, and potassium supplementation may be required.

The effectiveness of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide. Dosage adjustments of the anticoagulant may be necessary based on clinical response and monitoring of coagulation parameters.

Triamterene and hydrochlorothiazide may elevate blood uric acid levels, necessitating dosage adjustments of antigout medications in patients with a history of gout.

Triamterene and quinidine share similar fluorescence spectra, which may interfere with the fluorescent measurement of quinidine when used together. Alternative monitoring methods should be considered.

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

Chronic or excessive use of laxatives may lead to reduced serum potassium levels by promoting excessive potassium loss from the intestinal tract. Patients should be monitored for potassium levels, and appropriate supplementation should be considered if necessary.

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, are at an increased risk for hyperkalemia, especially when they have renal impairment or diabetes, even in the absence of renal impairment. Due to these heightened risks, serum potassium levels must be monitored at frequent intervals in this population, as well as in patients with impaired renal function.

Clinical studies have demonstrated that the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced in elderly patients, leading to increased plasma levels of these medications. Therefore, careful consideration should be given to dosage adjustments in geriatric patients to mitigate the risk of adverse effects.

Additionally, 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 essential to ensure the safe and effective use of these medications in the geriatric population.

Pregnancy

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

Animal reproduction studies may not reliably predict human responses; thus, triamterene should be used during pregnancy only when clearly necessary. Similarly, hydrochlorothiazide should be prescribed during pregnancy only if clearly needed, given the lack of sufficient data from controlled studies in this population.

Both thiazides and triamterene are known to cross the placental barrier and can be detected in cord blood. The use of these agents in pregnant patients necessitates careful consideration of the anticipated benefits against potential hazards to the fetus. Possible risks associated with their use 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 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 developing hyperkalemia is heightened in patients receiving potassium-sparing diuretics, particularly in those with renal impairment. For patients with mild renal functional impairment, the use of this medication should be approached with caution and accompanied by continuous 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 monitored closely when using triamterene and hydrochlorothiazide.

Additionally, potassium-sparing therapy should be avoided in severely ill patients who may experience respiratory or metabolic acidosis. If triamterene and hydrochlorothiazide is prescribed, frequent evaluations of acid/base balance and serum electrolytes are essential to ensure patient safety.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to 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 prescribing information.

Overdosage

In cases of overdosage, electrolyte imbalance is the primary concern, manifesting through a range of symptoms. These may include polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes.

Immediate intervention is critical. Healthcare professionals should induce evacuation of the stomach through emesis or gastric lavage as soon as an overdose is suspected. 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 of a formulation containing 50 mg of triamterene and 25 mg of hydrochlorothiazide. While triamterene is predominantly protein-bound (approximately 67%), there may still be some benefit to dialysis in managing cases of overdosage.

Prompt recognition and management of these symptoms and interventions are essential to mitigate the risks associated with overdose.

Nonclinical Toxicology

Animal reproduction studies to assess the potential for fetal harm associated with triamterene and hydrochlorothiazide have not been conducted. However, a One Generation Study in rats, utilizing a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day), demonstrated no evidence of teratogenicity at these doses, which 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 safety of triamterene and hydrochlorothiazide during pregnancy has not been established due to the absence of adequate and well-controlled studies in pregnant women. Therefore, the use of these agents in pregnancy should only occur if the potential benefits justify the risks to the fetus.

Reproduction studies 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 revealed no evidence of fetal harm attributable to triamterene. Hydrochlorothiazide was administered orally to pregnant mice and rats during critical periods of organogenesis at doses reaching 3,000 mg/kg/day for mice and 1,000 mg/kg/day for rats. At these doses, which are significantly higher than the MRHD (3,000 times for mice and 1,000 times for rats based on body weight, and 282 and 206 times based on body surface area, respectively), no evidence of fetal harm was observed.

Thiazides and triamterene have been shown to cross the placental barrier and can be detected in cord blood. The use of these medications 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 evaluating the combination of triamterene and hydrochlorothiazide, or triamterene alone, have not been performed. Two-year feeding studies conducted by the National Toxicology Program (NTP) involved administering hydrochlorothiazide to mice and rats at doses of up to 600 mg/kg/day and 100 mg/kg/day, respectively. These doses correspond to 600 times the MRHD for hydrochlorothiazide in mice and 100 times in rats based on body weight, and 56 times and 21 times the MRHD based on body surface area. These studies did not reveal any carcinogenic potential of hydrochlorothiazide in rats or female mice; however, equivocal evidence of hepatocarcinogenicity was noted in male mice.

No studies have been conducted to evaluate the mutagenic potential of the triamterene and hydrochlorothiazide combination or of triamterene alone. Hydrochlorothiazide was not found to be genotoxic in various in vitro assays, including the Ames test and tests for chromosomal aberrations in Chinese Hamster Ovary (CHO) cells, as well as in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. Positive results were observed in the in vitro CHO Sister Chromatid Exchange test and in mouse Lymphoma Cell assays at hydrochlorothiazide concentrations ranging from 43 to 1,300 mcg/mL. Additionally, positive results were obtained in the Aspergillus nidulans nondisjunction assay.

Studies assessing the effects of the triamterene and hydrochlorothiazide combination or triamterene alone on animal reproductive function have not been conducted. However, 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 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. These doses correspond to 100 times the MRHD for mice and 4 times for rats based on body weight, and 9.4 times for mice and 0.8 times for rats based on body surface area.

Postmarketing Experience

Hydrochlorothiazide has been associated with 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 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 to ensure its integrity. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture and light to maintain its efficacy. Additionally, it must be kept out of reach of children to ensure safety.

Additional Clinical Information

Laboratory tests are essential for monitoring patients on triamterene and hydrochlorothiazide. Serum potassium levels should be maintained within the normal adult range of 3.5 to 5.0 mEq/L, with corrective measures such as potassium supplementation or dietary adjustments implemented cautiously if hypokalemia occurs. Persistent elevations above 6 mEq/L necessitate careful observation and treatment, and any abnormal increase in serum potassium should prompt immediate discontinuation of corrective measures. If potassium levels remain abnormal, triamterene and hydrochlorothiazide should be replaced with a thiazide diuretic until normalization is achieved.

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 should be discontinued prior to parathyroid function tests, as they reduce calcium excretion. While some patients on prolonged thiazide therapy have shown pathologic changes in parathyroid glands, common complications of hyperparathyroidism have not been observed.

FDA Insert (PDF)

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

View full prescribing information (PDF)