Triamterene and Hydrochlorothiazide (Capsule)

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The usual dose of triamterene and hydrochlorothiazide capsules is one or two capsules given once daily, with appropriate monitoring of serum potassium and of the clinical effect.

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 andits 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 chlorideions 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, the following mean pharmacokinetic parameters were determined: 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. One triamterene and hydrochlorothiazide capsule 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), hydrochlorothiazideby 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.<br/>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 five 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.

Antikaliuretic Therapy and Potassium Supplementation: Triamterene and hydrochlorothiazide capsules should not be given to patients receiving other potassium-sparing agents such as spironolactone, amiloride or other formulations containing triamterene. Concomitant potassium-containing salt substitutes should also not be used. Potassium supplementation should not be used with triamterene and hydrochlorothiazide capsules except in severe cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary.<br/>Impaired Renal Function: Triamterene and hydrochlorothiazide capsules are contraindicated in patients with anuria, acute and chronic renal insufficiency or significant renal impairment.<br/>Hypersensitivity: Hypersensitivity to either drug in the preparation or to other sulfonamide-derived drugs is a contraindication.<br/>Hyperkalemia: Triamterene and hydrochlorothiazide capsules should not be used in patients with preexisting elevated serum potassium.

Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide capsules. Hyperkalemia is more likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment), and in the elderly or severelyill. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving triamterene and hydrochlorothiazide capsules, when dosages are changed or with any illness that may influence renal function.

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Electrolyte imbalance is the major concern . Symptoms reported include: polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face and hyperactive deep tendon reflexes. If hypotension occurs, it may be treated with pressor agents such as norepinephrine to maintain blood pressure. Carefully evaluate the electrolyte pattern and fluid balance. Induce immediate evacuation of the stomach through emesis or gastric lavage. There is no specific antidote. Reversible acute renal failure following ingestion of 50 tablets of a product containing a combination of 50 mg triamterene and 25 mg hydrochlorothiazide has been reported. Although triamterene is largely protein-bound (approximately 67%), there may be some benefit to dialysis in cases of overdosage.

Triamterene and Hydrochlorothiazide (Capsule)

Hyperkalemia: Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide capsules. Hyperkalemia is more likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment), and in the elderly or severelyill. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving triamterene and hydrochlorothiazide capsules, when dosages are changed or with any illness that may influence renal function. If hyperkalemia is suspected (warning signs include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because hyperkalemia may not be associated with ECG changes. If hyperkalemia is present, triamterene and hydrochlorothiazide capsules should be discontinued immediately and a thiazide alone should be substituted. If the serum potassium exceeds 6.5 mEq/liter more vigorous therapy is required. The clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis. The development of hyperkalemia associated with potassium-sparing diuretics is accentuated in the presence of renal impairment . Patients with mild renal functional impairment should not receive this drug without frequent and continuing monitoring of serum electrolytes. Cumulative drug effects may be observed in patients with impaired renal function. The renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, the sulfate ester of hydroxytriamterene, have been shown to be reduced and the plasma levels increased following triamterene and hydrochlorothiazide administration to elderly patients and patients with impaired renal function. Hyperkalemia has been reported in diabetic patients with the use of potassium-sparing agents even in the absence of apparent renal impairment. Accordingly, serum electrolytes must be frequently monitored if triamterene and hydrochlorothiazide capsules are used in diabetic patients.<br/>Metabolic or Respiratory Acidosis: Potassium-sparing therapy should also be avoided in severely ill patients in whom respiratory or metabolic acidosis may occur. Acidosis may be associated with rapid elevations in serum potassium levels. If triamterene and hydrochlorothiazide capsules are employed, frequent evaluations of acid/base balance and serum electrolytes are necessary.

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Triamterene and Hydrochlorothiazide