Prescription Drug Information: Triamterene and Hydrochlorothiazide

TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide tablet
PD-Rx Pharmaceuticals, Inc.

DESCRIPTION

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

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

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

Triamterene and hydrochlorothiazide tablets for oral administration contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. In addition, the 37.5 mg/25 mg tablets contain D&C Yellow No.10 Aluminum Lake and FD&C Blue No.1 Aluminum Lake.

Triamterene is 2,4,7-triamino-6-phenylpteridine. Triamterene is practically insoluble in water, benzene, chloroform, ether and dilute alkali hydroxides. It is soluble in formic acid and sparingly soluble in methoxyethanol. Triamterene is very slightly soluble in acetic acid, alcohol and dilute mineral acids. The following is the structural formula:

structure-triamterene
(click image for full-size original)

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4, benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform and dilute mineral acids. Its molecular weight is 297.73. The following is the structural formula:

structure-hydrochlorothiazide
(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 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 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 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 this product 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 Apotex’s triamterene and hydrochlorothiazide 37.5 mg/25 mg or 75 mg/50 mg 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 are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.

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

Usage in Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

CONTRAINDICATIONS

Hyperkalemia

Triamterene and hydrochlorothiazide should not be used in the presence of elevated serum potassium levels (greater than or equal to 5.5 mEq/liter). If hyperkalemia develops, this drug should be discontinued, and a thiazide alone should be substituted.

Antikaliuretic Therapy or Potassium Supplementation

Triamterene and hydrochlorothiazide should not be given to patients receiving other potassium-conserving agents such as spironolactone, amiloride hydrochloride or other formulations containing triamterene. Concomitant potassium supplementation in the form of medication, potassium-containing salt substitute or potassium-enriched diets should also not be used.

Impaired Renal Function

Triamterene and hydrochlorothiazide is contraindicated in patients with anuria, acute and chronic renal insufficiency or significant renal impairment.

Hypersensitivity

Triamterene and hydrochlorothiazide should not be used in patients who are hypersensitive to triamterene or hydrochlorothiazide or other sulfonamide-derived drugs.

WARNINGS

Hyperkalemia

Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-conserving diuretic combinations, including triamterene and hydrochlorothiazide. Hyperkalemia is more likely to occur in patients with renal impairment, diabetes (even without evidence of renal impairment), or elderly or severely ill patients. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving triamterene and hydrochlorothiazide, 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 mild hyperkalemia may not be associated with ECG changes.

If hyperkalemia is present, triamterene and hydrochlorothiazide 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 (see CONTRAINDICATIONS). 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-conserving agents even in the absence of apparent renal impairment. Accordingly, triamterene and hydrochlorothiazide should be avoided in diabetic patients. If it is employed, serum electrolytes must be frequently monitored.

Because of the potassium-sparing properties of angiotensin-converting enzyme (ACE) inhibitors, triamterene and hydrochlorothiazide should be used cautiously, if at all, with these agents (see PRECAUTIONS, Drug Interactions).

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