Triamterene and Hydrochlorothiazide Tablets, USP
Rx only

Triamterene and Hydrochlorothiazide Tablets for oral administration, combines triamterene, a potassium-conserving diuretic with the natriuretic agent, hydrochlorothiazide. Triamterene and hydrochlorothiazide tablets are available in two strengths. Each triamterene and hydrochlorothiazide tablet, 75 mg/50 mg, contains triamterene, USP, 75 mg and hydrochlorothiazide, USP, 50 mg. Each triamterene and hydrochlorothazide tablet, 37.5 mg/25 mg, contains triamterene, USP, 37.5 mg and hydrochlorothiazide, USP, 25 mg.

Both strengths of triamterene and hydrochlorothiazide tablets contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, polacrilin potassium, polyethylene glycol 8000, povidone, and magnesium stearate. Triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg also contain FD & C blue #2.

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. Its molecular weight is 253.27. Its structural formula is:

Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2H-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. Its structural formula is:

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 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 two hours and the peak action takes place in four hours. Diuretic activity persists for approximately six to twelve 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 levels are attained in approximately two 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 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 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 and 100 mg, resulted in no additional elevations in serum potassium levels. The dose response relationship of triamterene was also evaluated in patients rendered hypokalemia 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 Watson’s Triamterene and Hydrochlorothiazide Tablets. The hydrochlorothiazide component of triamterene and hydrochlorothiazide tablets is bioequivalent to single entity hydrochlorothiazide tablet formulations.

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.

• Triamterene and Hydrochlorothiazide Tablets are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.

• 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.

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 in 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 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.

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.

Triamterene and hydrochlorothiazide should not be given to patients receiving other potassium-conserving agents such as spironolactone, amiloride HCI 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.

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

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

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 only 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 injection, sodium bicarbonate injection 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 function 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).

Metabolic or Respiratory Acidosis: Potassium-conserving 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 is employed, frequent evaluations of acid/base balance and serum electrolytes are necessary.

Thiazides may add to or potentiate the action of other antihypertensive drugs.

The thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazides have also been shown to increase responsiveness to tubocurarine.

Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Refer to the package insert on lithium before use of such concomitant therapy.

Acute renal failure has been reported in a few patients receiving indomethacin and formulations containing triamterene and hydrochlorothiazide. Caution is therefore advised when administering nonsteroidal anti-inflammatory agents with triamterene and hydrochlorothiazide.

Potassium-sparing agents, should be used cautiously, if at all, in conjunction with angiotensin-converting enzyme (ACE) inhibitors, due to an increased risk of hyperkalemia. Serum potassium should be monitored frequently.

Triamterene and quinidine have similar fluorescence spectra; thus, triamterene and hydrochlorothiazide may interfere with the measurement of quinidine.

Long term studies with triamterene/hydrochlorothiazide combination have not been conducted.

Studies of the mutagenic potential of triamterene and hydrochlorothiazide combination have not been performed.

Studies of the effect of triamterene/ hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted.

Animal reproduction studies to determine the potential for fetal harm by triamterene and hydrochlorothiazide tablets have not been conducted. Nevertheless, a One Generation Study in the rat approximated triamterene and hydrochlorothiazide’s composition by using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day). There was no evidence of teratogenicity at those doses that were, on a body-weight basis, 15 and 30 times, respectively, the MRHD, and, on the basis of body-surface area, 3.1 and 6.2 times, respectively, the MRHD.

The safe use of triamterene and hydrochlorothiazide tablets in pregnancy has not been established since there are no adequate and well-controlled studies with triamterene and hydrochlorothiazide tablets in pregnant women. Triamterene and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Thiazides and triamterene in combination have not been studied in nursing mothers. Triamterene appears in animal milk and this may occur in humans. Thiazides are excreted in human breast milk. If use of the combination drug product is deemed essential, the patient should stop nursing.

Safety and effectiveness in pediatric patients have not been established.

Side effects observed in association with the use of Triamterene and Hydrochlorothiazide Tablets, other combination products containing triamterene/ hydrochlorothiazide, and products containing triamterene or hydrochlorothiazide include the following:

Gastrointestinal: jaundice (intrahepatic cholestatic jaundice), pancreatitis, nausea, appetite disturbance, taste alteration, vomiting, diarrhea, constipation, anorexia, gastric irritation, cramping.

Central Nervous System: drowsiness and fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, paresthesias.

Cardiovascular: tachycardia, shortness of breath and chest pain, orthostatic hypotension (may be aggravated by alcohol, barbiturates or narcotics).

Renal: acute renal failure, acute interstitial nephritis, renal stones composed of triamterene in association with other calculus materials, urine discoloration.

Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia and megaloblastosis.

Ophthalmic: xanthopsia, transient blurred vision.

Hypersensitivity: anaphylaxis, photosensitivity, rash, urticaria, purpura, necrotizing angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis.

Other: muscle cramps and weakness, decreased sexual performance and sialadenitis.

Whenever adverse reactions are moderate to severe, therapy should be reduced or withdrawn.

Altered Laboratory Findings:

Serum Electrolytes: hyperkalemia, hypokalemia, hyponatremia, hypomagnesemia, hypochloremia (see WARNINGS, PRECAUTIONS).

Creatinine, Blood Urea Nitrogen: Reversible elevations in BUN and serum creatinine have been observed in hypertensive patients treated with triamterene and hydrochlorothiazide tablets.

Glucose: hyperglycemia, glycosuria and diabetes mellitus (see PRECAUTIONS).

Serum Uric Acids, PBI and Calcium: (see PRECAUTIONS).

Other: Elevated liver enzymes have been reported in patients receiving triamterene and hydrochlorothiazide tablets.

No specific data are available regarding triamterene and hydrochlorothiazide overdosage in humans and no specific antidote is available.

Fluid and electrolyte imbalances are the most important concern. Excessive doses of the triamterene component may be elicit hyperkalemia, dehydration, nausea, vomiting and weakness and possibly hypotension. Overdosing with hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, lethargy (may progress to coma) and gastrointestinal irritation. Treatment is symptomatic and supportive. Therapy with triamterene and hydrochlorothiazide should be discontinued. Induce emesis or institute gastric lavage. Monitor serum electrolyte levels and fluid balance. Institute supportive measures as required to maintain hydration, electrolyte balance, respiratory, cardiovascular, and renal function.

Note: 37.5 mg/25 mg = 37.5 mg triamterene and 25 mg hydrochlorothiazide

75 mg/50 mg = 75 mg triamterene and 50 mg hydrochlorothiazide

The usual dosage of Triamterene and Hydrochlorothiazide as a tablet is 37.5 mg/25 mg or 75 mg/50 mg daily, given as a single dose, with appropriate monitoring of serum potassium (see WARNINGS).There is no experience with the use of more than 75 mg/50 mg daily of triamterene and hydrochlorothiazide. Clinical experience with the administration of 37.5 mg/25 mg of triamterene and hydrochlorothiazide twice daily (in divided doses rather than as a single dose) suggests an increased risk of electrolyte imbalance and renal dysfunction.

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemia may be transferred to this 75 mg/50 mg product directly. Patients receiving 25 mg hydrochlorothiazide who become hypokalemic may be transferred to a 37.5 mg/25 mg product directly.

In patients requiring hydrochlorothiazide therapy and in whom hypokalemia cannot be risked, therapy may be initiated with 37.5 mg/25 mg of triamterene and hydrochlorothiazide. If an optimal blood pressure response is not obtained with 37.5 mg/25 mg of triamterene and hydrochlorothiazide, then the dose should be increased to 75 mg/50 mg daily as a single dose. If blood pressure still is not controlled, another antihypertensive agent may be added (see PRECAUTIONS, Drug Interactions).

Clinical studies have shown that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide in daily doses of 25 to 50 mg hydrochlorothiazide and 50 to 100 mg of triamterene may be safely changed to 37.5 mg/25 mg of triamterene and hydrochlorothiazide daily. All patients changed from less bioavailable formulations to this product should be monitored clinically and for serum potassium after the transfer.

Triamterene and Hydrochlorothiazide Tablets, USP, 37.5 mg/25 mg, are light green, round, scored tablets, debossed with Watson 424 and are available in bottles of:

30, NDC 52544-424-30
100, NDC 52544-424-01
500, NDC 52544-424-05

Triamterene and Hydrochlorothiazide Tablets, USP, 75 mg/50 mg, are yellow, round, scored tablets, debossed with Watson 348 and are available in bottles of:

30, NDC 52544-348-30
100, NDC 52544-348-01
500, NDC 52544-348-05
1000, NDC 52544-348-10

Bottles of 30 and 100 tablets are provided with child-resistant closures.

Store at controlled room temperature 15°C to 30°C (59°F to 86°F) protected from light.

Dispense in a tight, light-resistant container with a child-resistant closure.

Watson Laboratories, Inc.
Corona, CA 92880

11172-9
Rev: Jan. 2000