Caution should be exercised when administering DYAZIDE (hydrochlorothiazide and triamterene) to patients with diabetes, since thiazides may cause hyperglycemia, glycosuria, and alter insulin requirements in diabetes. Also, diabetes mellitus may become manifest during thiazide administration. Impaired Hepatic Function: Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease. Potassium depletion induced by the thiazide may be important in this connection. Administer DYAZIDE (hydrochlorothiazide and triamterene) cautiously and be alert for such early signs of impending coma as confusion, drowsiness, and tremor; if mental confusion increases discontinue DYAZIDE (hydrochlorothiazide and triamterene) for a few days. Attention must be given to other factors that may precipitate hepatic coma, such as blood in the gastrointestinal tract or preexisting potassium depletion.
Hypokalemia is uncommon with DYAZIDE (hydrochlorothiazide and triamterene) ; but, should it develop, corrective measures should be taken such as potassium supplementation or increased intake of potassium-rich foods. Institute such measures cautiously with frequent determinations of serum potassium levels, especially in patients receiving digitalis or with a history of cardiac arrhythmias. If serious hypokalemia (serum potassium less than 3.0 mEq/L) is demonstrated by repeat serum potassium determinations, DYAZIDE (hydrochlorothiazide and triamterene) should be discontinued and potassium chloride supplementation initiated. Less serious hypokalemia should be evaluated with regard to other coexisting conditions and treated accordingly.
Electrolyte imbalance, often encountered in such conditions as heart failure, renal disease or cirrhosis of the liver, may also be aggravated by diuretics and should be considered during therapy with DYAZIDE (hydrochlorothiazide and triamterene) 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 such warning signs 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. Renal Stones: Triamterene has been found in renal stones in association with the other usual calculus components. DYAZIDE (hydrochlorothiazide and triamterene) should be used with caution in patients with a history of renal stones.
Serum Potassium: The normal adult range of serum potassium is 3.5 to 5.0 mEq per liter 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 per liter 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 DYAZIDE (hydrochlorothiazide and triamterene) and substitute a thiazide diuretic alone until potassium levels return to normal.
Serum Creatinine and BUN: DYAZIDE (hydrochlorothiazide and triamterene) may produce an elevated blood urea nitrogen 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 DYAZIDE (hydrochlorothiazide and triamterene) is discontinued. If azotemia increases, discontinue DYAZIDE (hydrochlorothiazide and triamterene) . Periodic BUN or serum creatinine determinations should be made, especially in elderly patients and in patients with suspected or confirmed renal insufficiency.
Serum PBI: Thiazide may decrease serum PBI levels without sign of thyroid disturbance.
Parathyroid Function: 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Long-term studies have not been conducted with DYAZIDE (hydrochlorothiazide and triamterene) (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 DYAZIDE (hydrochlorothiazide and triamterene) at 50 mg/day (or 1.0 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.
Mutagenesis: Studies of the mutagenic potential of DYAZIDE (hydrochlorothiazide and triamterene) (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 1300 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 DYAZIDE (hydrochlorothiazide and triamterene) (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.
Category C: Teratogenic Effects: DYAZIDE (hydrochlorothiazide and triamterene) : Animal reproduction studies to determine the potential for fetal harm by DYAZIDE (hydrochlorothiazide and triamterene) have not been conducted. However, a One Generation Study in the rat approximated composition of DYAZIDE (hydrochlorothiazide and triamterene) by using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day); there was no evidence of teratogenicity at those doses which were, on a body-weight basis, 15 and 30 times, respectively, the MRHD, and on the basis of body-surface area, 3.1 and 6.2 times, respectively, the MRHD.
The safe use of DYAZIDE (hydrochlorothiazide and triamterene) in pregnancy has not been established since there are no adequate and well-controlled studies with DYAZIDE (hydrochlorothiazide and triamterene) in pregnant women. DYAZIDE (hydrochlorothiazide and triamterene) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Triamterene: Reproduction studies have been performed in rats at doses as high as 20 times the MRHD on the basis of body-weight, and 6 times the human dose on the basis of body-surface area without evidence of harm to the fetus due to triamterene.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Hydrochlorothiazide: Hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3,000 and 1,000 mg/kg/day, respectively. 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 equal to 282 for mice and 206 for rats, based on body-surface area, there was no evidence of harm to the fetus.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: 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 requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possible other adverse reactions which have occurred in the adult.
Thiazides and triamterene in combination have not been studied in nursing mothers. Triamterene appears in animal milk; this may occur in humans. Thiazides are excreted in human breast milk. If use of the combination drug product is deemed essential, the patient should stop nursing.
Safety and effectiveness in pediatric patients have not been established.