Triamterene and Hydrochlorothiazide

TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide tablet
Preferred Pharmaceuticals Inc.

DESCRIPTION

Triamterene and hydrochlorothiazide combines triamterene a potassium-conserving diuretic, with the natriuretic agent, hydrochlorothiazide.

Each Triamterene and Hydrochlorothiazide Tablet USP, 37.5 mg/25 mg contains:

Triamterene, USP ……………………………………………………………………37.5 mg

Hydrochlorothiazide, USP ……………………………………………………….25 mg

Each Triamterene and Hydrochlorothiazide Tablet USP, 75 mg/50 mg contains:

Triamterene, USP …………………………………………………………………..75 mg

Hydrochlorothiazide, USP ……………………………………………………….50 mg

Each triamterene and hydrochlorothiazide tablet, USP intended for oral administration contains 37.5 mg triamterene USP with 25 mg hydrochlorothiazide USP and 75 mg triamterene USP with 50 mg hydrochlorothiazide USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium stearate and microcrystalline cellulose. Additionally, the 37.5 mg/25 mg tablets contain FD&C Blue No. 1 Aluminum Lake.

Triamterene is 2,4,7-triamino-6-phenylpteridine. 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. Its molecular weight is 253.26. Its structural formula is:

figure
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Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H -1,2,4, benzothiadiazine-7-sulfonamide 1,1-dioxide. 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. Its molecular weight is 297.7. Its structural formula is:

figure
(click image for full-size original)

CLINICAL PHARMACOLOGY

Triamterene and hydrochlorothiazide is a diuretic, antihypertensive drug product, principally due to its hydrochlorothiazide component; the triamterene component of triamterene and hydrochlorothiazide reduces the excessive potassium loss which may occur with hydrochlorothiazide use.

Hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive agent. It blocks the renal tubular absorption of sodium and chloride ions. This natriuresis and diuresis is accompanied by a secondary loss of potassium and bicarbonate. Onset of hydrochlorothiazide’s diuretic effect occurs within 2 hours and the peak action takes place in 4 hours. Diuretic activity persists for approximately 6 to 12 hours.

The exact mechanism of hydrochlorothiazide’s antihypertensive action is not known although it may relate to the excretion and redistribution of body sodium. Hydrochlorothiazide does not affect normal blood pressure.

Following oral administration, peak hydrochlorothiazide plasma levels are attained in approximately 2 hours. It is excreted rapidly and unchanged in the urine.

Well controlled studies have demonstrated that doses of hydrochlorothiazide as low as 25 mg given once daily are effective in treating hypertension, but the dose-response has not been clearly established.

Triamterene

Triamterene is a potassium-conserving (antikaliuretic) diuretic with relatively weak natriuretic properties. It exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen. With this action, triamterene increases sodium excretion and reduces the excessive loss of potassium and hydrogen associated with hydrochlorothiazide. Triamterene is not a competitive antagonist of the mineralocorticoids and its potassium-conserving effect is observed in patients with Addison’s disease, i.e., without aldosterone. Triamterene’s onset and duration of activity is similar to hydrochlorothiazide. No predictable antihypertensive effect has been demonstrated with triamterene.

Triamterene is rapidly absorbed following oral administration. Peak plasma levels are achieved within one hour after dosing. Triamterene is primarily metabolized to the sulfate conjugate of hydroxytriamterene. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels.

The amount of triamterene added to 50 mg of hydrochlorothiazide in triamterene and hydrochlorothiazide tablets, 75 mg/50 mg was determined from steady-state dose-response evaluations in which various doses of liquid preparations of triamterene were administered to hypertensive persons who developed hypokalemia with hydrochlorothiazide (50 mg given once daily). Single daily doses of 75 mg triamterene resulted in greater increases in serum potassium than lower doses (25 mg and 50 mg), while doses greater than 75 mg of triamterene resulted in no additional elevations in serum potassium levels. The amount of triamterene added to the 25 mg of hydrochlorothiazide in triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg was also determined from steady-state dose-response evaluations in which various doses of liquid preparations of triamterene were administered to hypertensive persons who developed hypokalemia with hydrochlorothiazide (25 mg given once daily). Single daily doses of 37.5 mg triamterene resulted in greater increases in serum potassium than a lower dose (25 mg), while doses greater than 37.5 mg of triamterene, i.e., 75 mg and 100 mg, resulted in no additional elevations in serum potassium levels. The dose-response relationship of triamterene was also evaluated in patients rendered hypokalemic by hydrochlorothiazide given 25 mg twice daily. Triamterene given twice daily increased serum potassium levels in a dose related fashion. However, the combination of triamterene and hydrochlorothiazide given twice daily also appeared to produce an increased frequency of elevation in serum BUN and creatinine levels. The largest increases in serum potassium, BUN and creatinine in this study were observed with 50 mg of triamterene given twice daily, the largest dose tested. Ordinarily, triamterene does not entirely compensate for the kaliuretic effect of hydrochlorothiazide and some patients may remain hypokalemic while receiving triamterene and hydrochlorothiazide. In some individuals, however, it may induce hyperkalemia (see WARNINGS).

The triamterene and hydrochlorothiazide components of triamterene and hydrochlorothiazide tablets are well absorbed and are bioequivalent to liquid preparations of the individual components administered orally. Food does not influence the absorption of triamterene or hydrochlorothiazide from triamterene and hydrochlorothiazide tablets. The hydrochlorothiazide component of triamterene and hydrochlorothiazide tablets is bioequivalent to single entity hydrochlorothiazide tablet formulations.

INDICATIONS AND USAGE

This fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked.

1.
Triamterene and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.
2.
Triamterene and hydrochlorothiazide tablets, USP are also indicated for those patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked (e.g., patients on concomitant digitalis preparations, or with a history of cardiac arrhythmias, etc.).

Triamterene and hydrochlorothiazide tablets, USP may be used alone or in combination with other antihypertensive drugs, such as beta-blockers. Since triamterene and hydrochlorothiazide tablets, USP may enhance the actions of these drugs, dosage adjustments may be necessary.

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