Triamterene and Hydrochlorothiazide

TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide capsule
NuCare Pharmaceuticals,Inc.

DESCRIPTION

Each capsule of triamterene and hydrochlorothiazide for oral use, with opaque yellow cap and opaque white body, contains triamterene 37.5 mg and hydrochlorothiazide 25 mg, and is imprinted with 855. Hydrochlorothiazide is a diuretic/antihypertensive agent and triamterene is an antikaliuretic agent.

Hydrochlorothiazide, USP is very slightly soluble in water. It is freely soluble in sodium hydroxide solution, n-butylamine and dimethyl formamide. It is sparingly soluble in methanol. It is insoluble in ether, chloroform and dilute mineral acids.

Hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2 H-1, 2, 4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is:

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Triamterene, USP is soluble in formic acid. It is sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol and dilute mineral acids. It is practically insoluble in water, benzene, ether, chloroform and dilute alkali hydroxides.

Triamterene, USP is 2, 4, 7-triamino-6-phenylpteridine and its structural formula is:

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Each triamterene and hydrochlorothiazide capsule, USP intended for oral administration contains 37.5 mg triamterene USP with 25 mg hydrochlorothiazide USP. In addition, each capsule contains the following inactive ingredients: citric acid monohydrate, colloidal silicon dioxide, croscarmellose sodium, gelatin, glycine, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and titanium dioxide. Each capsule is printed with black pharmaceutical ink which contains ferric oxide black, potassium hydroxide and shellac.

Capsules of triamterene and hydrochlorothiazide meet Drug Release Test 3 as published in the current USP monograph for Triamterene and Hydrochlorothiazide Capsules.

CLINICAL PHARMACOLOGY

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 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 Volunteers a
AUC (0-48) ng*h/mL SD) C max ng/mL SD) Median T max 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 14.3 (3.8)

a AUC (0-48) , C max , T max, and Ae represent area under the plasma concentration versus time plot, maximum plasma concentration, time to reach C max , 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.

CLINICAL TRIALS

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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