Triamterene/Hydrochlorothiazide

Description

Triamterene and hydrochlorothiazide is a combination of triamterene, a potassium-conserving diuretic, and hydrochlorothiazide, a natriuretic agent. Each Triamterene and Hydrochlorothiazide Tablet USP is available in two strengths: 37.5 mg/25 mg and 75 mg/50 mg. The 37.5 mg/25 mg tablet contains 37.5 mg of triamterene, USP, and 25 mg of hydrochlorothiazide, USP, while the 75 mg/50 mg tablet contains 75 mg of triamterene, USP, and 50 mg of hydrochlorothiazide, USP.

The tablets are intended for oral administration and include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate, and microcrystalline cellulose. The 37.5 mg/25 mg tablets also contain FD&C Blue No. 1 Aluminum Lake.

Triamterene is chemically defined as 2,4,7-triamino-6-phenylpteridine, with a molecular weight of 253.26. It is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in acetic acid, alcohol, and dilute mineral acids. It is practically insoluble in water, benzene, ether, chloroform, and dilute alkali hydroxides. Hydrochlorothiazide is defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.7. Hydrochlorothiazide is very slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethyl formamide, and sparingly soluble in methanol. It is insoluble in ether, chloroform, and dilute mineral acids.

Uses and Indications

Triamterene and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension or edema in patients who develop hypokalemia while on hydrochlorothiazide monotherapy. This combination therapy is also appropriate for patients requiring a thiazide diuretic in whom the risk of hypokalemia must be minimized, such as those on concomitant digitalis preparations or with a history of cardiac arrhythmias.

Limitations of Use: The routine use of diuretics in otherwise healthy pregnant women is not recommended, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there sufficient evidence to support their efficacy in treating established toxemia.

In cases of edema during pregnancy, which may arise from pathological causes or the physiological and mechanical effects of pregnancy, thiazides may be indicated when the edema is due to pathological conditions, similar to their use in non-pregnant patients. Dependent edema resulting from venous return restriction due to an expanded uterus should be managed through non-pharmacological measures such as elevating the lower extremities and using support hose. The hypervolemia associated with normal pregnancy is typically not harmful to the mother or fetus, provided there is no underlying cardiovascular disease, and is often accompanied by generalized edema in many pregnant women. If this edema causes significant discomfort, increased recumbency may offer relief. In rare instances where extreme discomfort persists despite rest, a short course of diuretics may be considered appropriate.

Dosage and Administration

The usual dose of triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg, is one or two tablets daily, administered as a single dose. Serum potassium levels should be monitored appropriately during treatment. For the 75 mg/50 mg formulation, the recommended dosage is one tablet daily, also with appropriate monitoring of serum potassium.

There is no clinical experience supporting the use of more than one 75 mg/50 mg tablet daily or more than two 37.5 mg/25 mg tablets daily. It is important to note that administering two 37.5 mg/25 mg tablets daily in divided doses, rather than as a single dose, may increase the risk of electrolyte imbalance and renal dysfunction.

For patients currently receiving 50 mg of hydrochlorothiazide who become hypokalemic, a direct transfer to triamterene and hydrochlorothiazide tablets, 75 mg/50 mg, is recommended. Similarly, patients on 25 mg of hydrochlorothiazide who experience hypokalemia may be transitioned directly to triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg.

In cases where patients require hydrochlorothiazide therapy but cannot risk hypokalemia, treatment may be initiated with triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg. If optimal blood pressure response is not achieved with this dosage, the dose may be increased to two 37.5 mg/25 mg tablets daily as a single dose or one tablet of triamterene and hydrochlorothiazide tablets, 75 mg/50 mg, daily. Should blood pressure remain uncontrolled, the addition of another antihypertensive agent should be considered.

Patients transitioning from less bioavailable formulations to triamterene and hydrochlorothiazide tablets, 75 mg/50 mg, should be closely monitored both clinically and for serum potassium levels following the transfer.

Contraindications

Triamterene and hydrochlorothiazide are contraindicated in the following situations:

Use is contraindicated in patients with elevated serum potassium levels (≥ 5.5 mEq/liter) due to the risk of hyperkalemia. If hyperkalemia develops, the medication should be discontinued, and a thiazide alone should be substituted.

Concomitant use with other potassium-conserving agents, such as spironolactone or amiloride hydrochloride, is contraindicated. Additionally, potassium supplementation through medications, potassium-containing salt substitutes, or potassium-enriched diets should not be utilized.

This combination 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 triamterene, hydrochlorothiazide, or other sulfonamide-derived drugs also contraindicates the use of this medication.

Warnings and Precautions

Hyperkalemia, characterized by an abnormal elevation of serum potassium levels (≥ 5.5 mEq/liter), poses a significant risk with the use of potassium-conserving diuretic combinations, including triamterene and hydrochlorothiazide. This condition is particularly prevalent in patients with renal impairment, diabetes (even in the absence of renal impairment), as well as in elderly or severely ill individuals. Due to the potential for uncorrected hyperkalemia to be fatal, it is imperative that serum potassium levels are monitored at frequent intervals. This is especially critical for patients who are newly prescribed triamterene and hydrochlorothiazide, during any dosage adjustments, or in the presence of any illness that may affect renal function.

Regular monitoring of serum potassium levels is essential to ensure patient safety and to mitigate the risk of hyperkalemia. Healthcare professionals should remain vigilant in assessing these levels, particularly during the initiation of therapy or when changes in dosage occur.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The following sections categorize these reactions based on their seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, which can manifest as respiratory distress, including pneumonitis, and other symptoms like rash, urticaria, purpura, and necrotizing angiitis (vasculitis, cutaneous vasculitis). Hematologic reactions may also occur, including leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, and megaloblastosis. Renal complications such as acute renal failure and acute interstitial nephritis have been reported, alongside the formation of renal stones composed of triamterene. Patients may also experience hyperkalemia, particularly those with renal impairment, diabetes, or those who are elderly or severely ill. This condition necessitates frequent monitoring of serum potassium levels, especially when initiating treatment or adjusting dosages.

Common adverse reactions reported in clinical trials and postmarketing experiences include gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation, and appetite disturbance. Patients may also experience jaundice (intrahepatic cholestatic jaundice) and gastric irritation. Central nervous system effects are prevalent, with participants reporting drowsiness, fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, and paresthesias. Cardiovascular reactions may include tachycardia, shortness of breath, chest pain, and orthostatic hypotension, which can be exacerbated by alcohol, barbiturates, or narcotics.

Ophthalmic effects such as xanthopsia and transient blurred vision have been noted. Other reactions include muscle cramps, weakness, decreased sexual performance, and sialadenitis.

Additionally, elevated liver enzymes have been observed in patients receiving this treatment. It is important to note that hydrochlorothiazide, a component of the combination therapy, is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The risk for SCC in the overall population is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥ 50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

Patients should be monitored closely for these adverse reactions, and any significant changes in health status should be reported to a healthcare provider.

Drug Interactions

Thiazide diuretics may enhance the effects of other antihypertensive agents, potentially leading to additive hypotensive effects. Clinicians should monitor blood pressure closely when initiating or adjusting therapy with thiazides in patients already receiving antihypertensive medications.

Thiazides have been observed to decrease arterial responsiveness to norepinephrine; however, this effect does not compromise the therapeutic efficacy of norepinephrine as a pressor agent. Additionally, thiazides may increase the responsiveness to neuromuscular blocking agents such as tubocurarine, necessitating careful monitoring of neuromuscular function during concurrent use.

Concomitant use of lithium with diuretics, including thiazides, is generally contraindicated due to the potential for reduced renal clearance of lithium, which significantly increases the risk of lithium toxicity. It is advisable to consult the package insert for lithium prior to considering this combination therapy.

Caution is warranted when administering non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin in patients receiving triamterene and hydrochlorothiazide, as acute renal failure has been reported in some cases. Monitoring of renal function is recommended in these patients.

The combination of potassium-sparing agents with angiotensin-converting enzyme (ACE) inhibitors should be approached with extreme caution due to the significantly elevated risk of hyperkalemia. Frequent monitoring of serum potassium levels is essential in patients receiving both classes of medications to prevent potential complications.

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 if they have renal impairment or diabetes, even in the absence of renal impairment. It is essential to monitor serum potassium levels at frequent intervals in this population, particularly when initiating treatment with triamterene and hydrochlorothiazide, when dosages are adjusted, or during any illness that may affect renal function.

In elderly patients, the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene are reduced, leading to increased plasma levels of these medications. Therefore, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, as elevations in these parameters may occur more frequently in geriatric patients.

Additionally, cumulative drug effects may be observed in elderly patients with impaired renal function, necessitating careful monitoring and potential dose adjustments to mitigate the risk of adverse effects.

Pregnancy

The use of triamterene and hydrochlorothiazide during pregnancy has not been established as safe due to the absence of adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted to assess the potential for fetal harm specifically from the combination of these two agents. 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 doses that were 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.

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 MRHD based on body-surface area, also without evidence of fetal harm. Hydrochlorothiazide has been administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 mg/kg/day for mice and 1000 mg/kg/day for rats, which are significantly higher than the MRHD. These studies similarly showed no evidence of harm to the fetus.

Despite these findings in animal studies, it is important to note that animal reproduction studies are not always predictive of human response. Therefore, triamterene and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Healthcare professionals are advised to carefully consider the necessity of this medication in pregnant patients.

Lactation

Triamterene and thiazides have not been studied in nursing mothers. However, triamterene is known to appear in animal milk, suggesting that it may also be excreted in human breast milk. Thiazides are confirmed to be excreted in human breast milk as well.

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

Renal Impairment

Patients with renal impairment are at an increased risk for hyperkalemia, defined as an abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter), particularly when treated with potassium-conserving diuretic combinations such as triamterene and hydrochlorothiazide. The likelihood of developing hyperkalemia is further heightened in patients with diabetes, even in the absence of renal impairment, as well as in elderly or severely ill patients.

It is essential to monitor serum potassium levels at frequent intervals in patients with reduced kidney function, especially during the initiation of therapy with triamterene and hydrochlorothiazide, following any dosage adjustments, or in the presence of any illness 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 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 with triamterene and hydrochlorothiazide, it is important to note that specific data regarding human overdosage are lacking, and no specific antidote is available. The primary concern in such situations is the potential for fluid and electrolyte imbalances.

Excessive doses of the triamterene component may lead to hyperkalemia, dehydration, nausea, vomiting, weakness, and possibly hypotension. Conversely, overdosing with hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, and lethargy, which may progress to coma, as well as gastrointestinal irritation.

Management of overdosage is primarily symptomatic and supportive. It is recommended that therapy with triamterene and hydrochlorothiazide be discontinued immediately. Healthcare professionals should consider inducing emesis or performing gastric lavage to mitigate the effects of the overdose.

Continuous monitoring of serum electrolyte levels and fluid balance is essential. Supportive measures should be instituted as necessary to maintain hydration, electrolyte balance, and the proper functioning of respiratory, cardiovascular, and renal systems.

Nonclinical Toxicology

Thiazides and triamterene have demonstrated the ability to cross the placental barrier, resulting in their presence in cord blood. The administration of these agents in pregnant women necessitates a careful evaluation of the anticipated benefits in relation to potential risks to the fetus.

Potential hazards associated with the use of thiazides and triamterene during pregnancy include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have been observed in adult populations.

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 notably observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of 50,000 mg or more demonstrate a heightened risk, with an estimated 1 additional case of SCC occurring 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 seeking shade when outdoors. Additionally, it is important for healthcare providers to recommend that patients undergo regular skin cancer screenings, as hydrochlorothiazide may increase the risk of skin cancer. Patients should be made aware of the importance of monitoring their skin for any changes and to report any unusual lesions or changes in moles to their healthcare provider promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the USP. It should be stored at a temperature range of 20º to 25º C (68º to 77º 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

Serum potassium levels should be monitored frequently in patients initiating treatment with triamterene and hydrochlorothiazide, during dosage adjustments, or when any condition may affect renal function. Clinicians are advised to perform serum electrolyte determinations at appropriate intervals to identify potential imbalances. Additionally, periodic assessments of blood urea nitrogen (BUN) and creatinine levels are recommended, particularly for elderly patients or those with suspected or confirmed hepatic or renal impairments.

Patients prescribed hydrochlorothiazide should be counseled on the importance of sun protection and regular skin cancer screenings. It is important to note that hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients receiving high cumulative doses. The overall risk for SCC in the general population is approximately one additional case per 16,000 patients per year, while white patients on a cumulative dose of 50,000 mg or more face an increased risk of one additional case per 6,700 patients per year.

FDA Insert (PDF)

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

View full prescribing information (PDF)