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Contents : NDA 16042/S-077 Page 3 PRESCRIBING INFORMATION Dyazide (hydrochlorothiazide/triamterene) Capsules DESCRIPTION Each capsule of Dyazide (hydrochlorothiazide and triamterene) for oral use with opaque red cap and opaque white body contains hydrochlorothiazide 25 mg and triamterene 37.5 mg and is imprinted with the product name Dyazide and SB. Hydrochlorothiazide is a diuretic/antihypertensive agent and triamterene is an antikaliuretic agent. Hydrochlorothiazide is slightly soluble in water. It is soluble in dilute ammonia dilute aqueous sodium hydroxide and dimethylformamide. It is sparingly soluble in methanol. Hydrochlorothiazide is 6-chloro-3 4-dihydro-2H-1 2 4-benzothiadiazine-7-sulfonamide 1 1 dioxide and its structural formula is: At 50 C triamterene is practically insoluble in water (less than 0.1%). It is soluble in formic acid sparingly soluble in methoxyethanol and very slightly soluble in alcohol. Triamterene is 2 4 7-triamino-6-phenylpteridine and its structural formula is: Inactive ingredients consist of benzyl alcohol cetylpyridinium chloride D&C Red No. 33 FD&C Yellow No. 6 gelatin glycine lactose magnesium stearate microcrystalline cellulose povidone polysorbate 80 sodium starch glycolate titanium dioxide and trace amounts of other inactive ingredients. Capsules of Dyazide meet Drug Release Test 3 as published in the current USP monograph for Triamterene and Hydrochlorothiazide Capsules. NDA 16042/S-077 Page 4 CLINICAL PHARMACOLOGY Dyazide 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 Dyazide 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 Dyazide are similar. Onset of diuresis with Dyazide takes place within 1 hour peaks at 2 to 3 hours and tapers off during the subsequent 7 to 9 hours. Dyazide is well absorbed. Upon administration of a single oral dose to fasted normal male volunteers the following mean pharmacokinetic parameters were determined: NDA 16042/S-077 Page 5 Triamterene AUC(0-48) ng*hrs/mL ( SD) 148.7 (87.9) Cmax ng/mL ( SD) 46.4 (29.4) Median Tmax Hrs 1.1 Ae Mg ( SD) 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) where 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 Dyazide 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 Dyazide with a high-fat meal resulted in: (1) an increase in the mean bioavailability of tria

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