Source: FDA, National Drug Code (US) Revision Year: 2023
The triamterene and hydrochlorothiazide capsule is a diuretic/antihypertensive drug product that combines natriuretic and antikaliuretic effects. Each component complements the action of the other. The hydrochlorothiazide component blocks the reabsorption of sodium and chloride ions, and thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. A portion of the additional sodium presented to the distal tubule is exchanged there for potassium and hydrogen ions. With continued use of hydrochlorothiazide and depletion of sodium, compensatory mechanisms tend to increase this exchange and may produce excessive loss of potassium, hydrogen, and chloride ions. Hydrochlorothiazide also decreases the excretion of calcium and uric acid, may increase the excretion of iodide, and may reduce glomerular filtration rate. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known.
The triamterene component of triamterene and hydrochlorothiazide capsules exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen ions. Its natriuretic activity is limited by the amount of sodium reaching its site of action. Although it blocks the increase in this exchange that is stimulated by mineralocorticoids (chiefly aldosterone), it is not a competitive antagonist of aldosterone and its activity can be demonstrated in adrenalectomized rats and patients with Addison’s disease. As a result, the dose of triamterene required is not proportionally related to the level of mineralocorticoid activity but is dictated by the response of the individual patients and the kaliuretic effect of concomitantly administered drugs. By inhibiting the distal tubular exchange mechanism, triamterene maintains or increases the sodium excretion and reduces the excess loss of potassium, hydrogen, and chloride ions induced by hydrochlorothiazide. As with hydrochlorothiazide, triamterene may reduce glomerular filtration and renal plasma flow. Via this mechanism, it may reduce uric acid excretion although it has no tubular effect on uric acid reabsorption or secretion. Triamterene does not affect calcium excretion. No predictable antihypertensive effect has been demonstrated for triamterene.
Duration of diuretic activity and effective dosage range of the hydrochlorothiazide and triamterene components of triamterene and hydrochlorothiazide capsules are similar. Onset of diuresis with triamterene and hydrochlorothiazide capsules takes place within 1 hour, peaks at 2 to 3 hours, and tapers off during the subsequent 7 to 9 hours.
Triamterene and hydrochlorothiazide capsules are well absorbed.
Upon administration of a single oral dose to fasted normal male volunteers, mean pharmacokinetic parameters were determined (Table 1).
Table 1. Mean Pharmacokinetic Parameters after Single Oral Dose in Fasted Male Volunteersa:
| AUC(0-48) ng*h/mL (± SD) | Cmax ng/mL (± SD) | Median Tmax h | Ae Mg (± SD) | |
|---|---|---|---|---|
| Triamterene | 148.7 (87.9) | 46.4 (29.4) | 1.1 | 2.7 (1.4) |
| Hydroxytriamterene sulfate | 1,865 (471) | 720 (364) | 1.3 | 19.7 (6.1) |
| Hydrochlorothiazide | 834 (177) | 135.1 (35.7) | 2.0 | 14.3 (3.8) |
a AUC(0-48), Cmax, Tmax, and Ae represent area under the plasma concentration versus time plot, maximum plasma concentration, time to reach Cmax, and amount excreted in urine over 48 hours.
A capsule of triamterene and hydrochlorothiazide is bioequivalent to a single entity 25-mg hydrochlorothiazide tablet and 37.5-mg triamterene capsule used in the double-blind clinical trial below (see Clinical Trials).
In a limited study involving 12 subjects, coadministration of triamterene and hydrochlorothiazide capsules with a high-fat meal resulted in: (1) an increase in the mean bioavailability of triamterene by about 67% (90% confidence interval = 0.99, 1.90), p-hydroxytriamterene sulfate by about 50% (90% confidence interval = 1.06, 1.77), hydrochlorothiazide by about 17% (90% confidence interval = 0.90, 1.34); (2) increases in the peak concentrations of triamterene and p-hydroxytriamterene; and (3) a delay of up to 2 hours in the absorption of the active constituents.
Long-term studies have not been conducted with triamterene and hydrochlorothiazide capsules (the triamterene/hydrochlorothiazide combination) or with triamterene alone.
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 1.0 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.
Studies of the mutagenic potential of triamterene and hydrochlorothiazide capsules (the triamterene/hydrochlorothiazide combination) or of triamterene alone have not been performed.
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.
Studies of the effects of triamterene and hydrochlorothiazide capsules (the triamterene/hydrochlorothiazide combination) or of triamterene alone on animal reproductive function have not been conducted.
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.
A placebo-controlled, double-blind trial was conducted to evaluate the efficacy of triamterene and hydrochlorothiazide capsules. This trial demonstrated that triamterene and hydrochlorothiazide capsules (37.5 mg triamterene/25 mg hydrochlorothiazide) were effective in controlling blood pressure while reducing the incidence of hydrochlorothiazide-induced hypokalemia. This trial involved 636 patients with mild to moderate hypertension controlled by hydrochlorothiazide 25 mg daily and who had hypokalemia (serum potassium <3.5 mEq/L) secondary to the hydrochlorothiazide. Patients were randomly assigned to 4 weeks' treatment with once-daily regimens of 25 mg hydrochlorothiazide plus placebo, or 25 mg hydrochlorothiazide combined with one of the following doses of triamterene: 25 mg, 37.5 mg, 50 mg, or 75 mg.
Blood pressure and serum potassium were monitored at baseline and throughout the trial. All 5 treatment groups had similar mean blood pressure and serum potassium concentrations at baseline (mean systolic blood pressure range: 137 ± 14 mmHg to 140 ± 16 mmHg; mean diastolic blood pressure range: 86 ± 9 mmHg to 88 ± 8 mmHg; mean serum potassium range: 2.3 to 3.4 mEq/L with the majority of patients having values between 3.1 and 3.4 mEq/L).
While all triamterene regimens reversed hypokalemia, at Week 4 the 37.5-mg regimen proved optimal compared with the other tested regimens. On this regimen, 81% of the patients had a significant (P<0.05) reversal of hypokalemia vs. 59% of patients on the placebo/hydrochlorothiazide regimen. The mean serum potassium concentration on 37.5-mg triamterene went from 3.2 ± 0.2 mEq/L at baseline to 3.7 ± 0.3 mEq/L at Week 4, a significantly greater (P<0.05) improvement than that achieved with placebo/hydrochlorothiazide (i.e., 3.2 ± 0.2 mEq/L at baseline and 3.5 ± 0.4 mEq/L at Week 4). Also, 51% of patients in the 37.5-mg triamterene group had an
increase in serum potassium of ≥0.5 mEq/L at Week 4 vs. 33% in the placebo group. The 37.5-mg triamterene/25-mg hydrochlorothiazide regimen also maintained control of blood pressure; mean supine systolic blood pressure at Week 4 was 138 ± 21 mmHg while mean supine diastolic blood pressure was 87 ± 13 mmHg.
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