Electrolyte imbalance, often encountered in conditions such as heart failure, renal disease, or cirrhosis of the liver, may also be aggravated by diuretics and should be considered during therapy with triamterene and hydrochlorothiazide when using high doses for prolonged periods or in patients on a salt-restricted diet. Serum determinations of electrolytes should be performed and are particularly important if the patient is vomiting excessively or receiving fluids parenterally. Possible fluid and electrolyte imbalance may be indicated by warning signs such as: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal symptoms.
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Triamterene has been found in renal stones in association with the other usual calculus components. Triamterene and hydrochlorothiazide capsules should be used with caution in patients with a history of renal stones.
The normal adult range of serum potassium is 3.5 to 5.0 mEq/L with 4.5 mEq often being used for a reference point. If hypokalemia should develop, corrective measures should be taken such as potassium supplementation or increased dietary intake of potassium-rich foods.
Institute such measures cautiously with frequent determinations of serum potassium levels. Potassium levels persistently above 6 mEq/L require careful observation and treatment. Serum potassium levels do not necessarily indicate true body potassium concentration. A rise in plasma pH may cause a decrease in plasma potassium concentration and an increase in the intracellular potassium concentration. Discontinue corrective measures for hypokalemia immediately if laboratory determinations reveal an abnormal elevation of serum potassium.
Discontinue triamterene and hydrochlorothiazide capsules and substitute a thiazide diuretic alone until potassium levels return to normal.
Serum Creatinine and Blood Urea Nitrogen
Triamterene and hydrochlorothiazide may produce an elevated blood urea nitrogen (BUN) level, creatinine level, or both. This apparently is secondary to a reversible reduction of glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia) rather than renal toxicity; levels usually return to normal when triamterene and hydrochlorothiazide capsules is discontinued. If azotemia increases, discontinue triamterene and hydrochlorothiazide capsules. Periodic BUN or serum creatinine determinations should be made, especially in elderly patients and in patients with suspected or confirmed renal insufficiency.
Serum Protein-Bound Iodine
Thiazide may decrease serum protein-bound iodine (PBI) levels without sign of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function. Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as bone resorption and peptic ulceration have not been seen.
Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.
Oral Hypoglycemic Drugs
Concurrent use with chlorpropamide may increase the risk of severe hyponatremia.
Nonsteroidal Anti-inflammatory Drugs
A possible interaction resulting in acute renal failure has been reported in a few patients on triamterene and hydrochlorothiazide capsules when treated with indomethacin, a nonsteroidal anti-inflammatory agent. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene and hydrochlorothiazide capsules.
Lithium generally should not be given with diuretics because they reduce its renal clearance and increase the risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy with triamterene and hydrochlorothiazide capsules.
Thiazides have been shown to decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently, caution should be observed in patients undergoing surgery
Concurrent use of hydrochlorothiazide with amphotericin B or corticosteroids or corticotropin (ACTH) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect.
Thiazides may add to or potentiate the action of other antihypertensive drugs. See INDICATIONS AND USAGE for concomitant use with other antihypertensive drugs.
The effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustments may be necessary.
Triamterene and hydrochlorothiazide may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout.
The following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain potassium up to 30 mEq/L of plasma or up to 65 mEq/L of whole blood when stored for more than 10 days); low-salt milk (may contain potassium up to 60 mEq/L); potassium-containing medications (such as parenteral penicillin G potassium); salt substitutes (most contain substantial amounts of potassium).
Exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake.
Chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene.
The effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.
Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.
Long-term studies have not been conducted with the triamterene/hydrochlorothiazide combination or with triamterene alone.
Hydrochlorothiazide: Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP) treated mice and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body-weight basis, these doses are 600 times (in mice) and 100 times (in rats) the maximum recommended human dose (MRHD) for the hydrochlorothiazide component of triamterene and hydrochlorothiazide capsules at 50 mg/day (or 1 mg/kg/day based on 50-kg individuals). On the basis of body surface area, these doses are 56 times (in mice) and 21 times (in rats) the MRHD. These studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
Studies of the mutagenic potential of the triamterene/hydrochlorothiazide combination or of triamterene alone have not been performed.
Hydrochlorothiazide: Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1,300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.
Impairment of Fertility
Studies of the effects of the triamterene/hydrochlorothiazide combination or of triamterene alone on animal reproductive function have not been conducted.
Hydrochlorothiazide: Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding multiples of the MRHD are 100 (mice) and 4 (rats) on the basis of body weight and 9.4 (mice) and 0.8 (rats) on the basis of body surface area.
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